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TRAF molecules in cell signaling and in human diseases

Ping Xie

Journal of Molecular Signaling · 2013 · Review · CC BY

doi:10.1186/1750-2187-8-7

Abstract

The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily. The past decade has witnessed rapid expansion of receptor families identified to employ TRAFs for signaling. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), T cell receptor, IL-1 receptor family, IL-17 receptors, IFN receptors and TGFβ receptors. In addition to their role as adaptor proteins, most TRAFs also act as E3 ubiquitin ligases to activate downstream signaling events. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-κBs (NF-κBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). Compelling evidence obtained from germ-line and cell-specific TRAF-deficient mice demonstrates that each TRAF plays indispensable and non-redundant physiological roles, regulating innate and adaptive immunity, embryonic development, tissue homeostasis, stress response, and bone metabolism. Notably, mounting evidence implicates TRAFs in the pathogenesis of human diseases such as cancers and autoimmune diseases, which has sparked new appreciation and interest in TRAF research. This review presents an overview of the current knowledge of TRAFs, with an emphasis on recent findings concerning TRAF molecules in signaling and in human diseases.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Background

The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily. There are six known members of the TRAF family (TRAF1 to 6) in mammals. Although a novel protein was named TRAF7, this claim is controversial as the protein does not have the TRAF homology domain that defines the TRAF family (Figure 1). The distinctive feature of all TRAF proteins is a C-terminal TRAF domain, which is composed of an N-terminal coiled-coil region (TRAF-N) and a C-terminal β-sandwich (TRAF-C). The TRAF domain mediates protein-protein interactions, including TRAF oligomerization as well as interactions with upstream regulators and downstream effectors. For example, the eight-stranded β-sandwich structure of the TRAF-C domain mediates the interaction with receptors, and the minor structural differences in this domain among TRAFs (as revealed by X-ray crystallography) define the specificity of each TRAF binding to various receptors. Therefore, one important role of TRAFs is to serve as adaptor proteins in the assembly of receptor-associated signaling complexes, linking upstream receptors to downstream effector enzymes. Most TRAFs, with the exception of TRAF1, contain an N-terminal RING finger domain, followed by a variable number of zinc fingers. The RING finger is found in many E3 ubiquitin ligases and comprises the core of the ubiquitin ligase catalytic domain. Indeed, increasing evidence indicates that in addition to their role as adaptor proteins, TRAFs (including TRAF2, 3, 5 and 6) also act as E3 ubiquitin ligases. Thus, TRAFs function as both adaptor proteins and E3 ubiquitin ligases to regulate signaling.

The past decade has witnessed rapid expansion of receptor families identified to employ TRAF proteins for signaling. In addition to the TNF-R superfamily, TRAFs are now recognized as signal transducers of a wide variety of other receptor families, including innate immune receptors, adaptive immune receptors, cytokine receptors, and C-type lectin receptors. For example, three major families of pattern recognition receptors (PRRs) of the innate immune system recruit TRAFs via additional adaptor proteins: Toll-like receptors (TLRs) via MyD88 or TRIF, nucleotide binding-oligomerization domain (NOD)-like receptors (NLRs) via RIP2, and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) via MAVS. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-κBs (NF-κB1 and NF-κB2), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). Acting alone or in combination, TRAFs are highly versatile regulators that control diverse cellular processes, including survival, proliferation, differentiation, activation, cytokine production, and autophagy.

Despite the similarities in the signaling pathways activated by different TRAF proteins, each TRAF appears to play obligatory and non-redundant physiological roles. Germ-line and conditional knockout mice have been instrumental in revealing the overlapping yet distinct roles of different TRAFs in whole animals. Compelling evidence from these studies demonstrates that TRAFs critically regulate a plethora of physiological processes, including innate and adaptive immunity, embryonic development, tissue homeostasis, stress response, and bone metabolism. The pivotal roles of TRAFs in host immunity are further highlighted by the discoveries that pathogens adopt deliberate strategies to subvert TRAF functions. An emerging paradigm of TRAF functions is that alterations in TRAFs may contribute to the pathogenesis of important human diseases, including cancers, autoimmune diseases and immunodeficiencies. This has sparked new appreciation and interest in TRAF research during the past few years. Here I attempt to provide an overview of the current knowledge of TRAFs, with an emphasis on recent advances in understanding TRAFs in receptor signaling and in human diseases as well as recent insights into the regulatory mechanisms of TRAF ubiquitination.

TRAFs in signaling by the TNF-R superfamily

Receptors of the TNF-R superfamily have wide tissue distribution and regulate diverse biological functions, including immune responses, inflammation, lymphoid organ and brain development, osteoclastogenesis, and tissue homeostasis. Structurally, these receptors are characterized by the presence of conserved cysteine-rich domains (CRDs) in their extracellular region that are responsible for the binding of their ligands of the TNF superfamily. Based on the intracellular structures, the TNF-R superfamily is categorized into two main groups. The first group of receptors, termed death receptors, contain a death domain in the intracellular region. The second group, also the majority of the TNF-R superfamily, do not have a death domain but contain TRAF-interacting motifs (TIMs) in their intracellular region. TRAF2, 3 and 5 usually have overlapping binding motifs, whereas TRAF6 has a distinct interacting motif on these receptors.

Receptors of this family do not have kinase activity and depend on the binding of adaptor proteins to assemble signaling complexes to activate downstream pathways. Signaling by death receptors mainly relies on adaptor proteins containing a death domain, such as TRADD or FADD, thereby culminating in caspase activation and cell apoptosis. In contrast, signaling by the TIM-containing receptors is mediated primarily, albeit not exclusively, via TRAFs. These include TRAFs that can interact with the receptors either directly through TIMs or indirectly through other TRAFs or adaptor proteins (Table 1). Binding of TRAFs to TNF-Rs typically induces signaling cascades leading to the activation of NF-κB and MAPKs, including ERK, p38 and JNK, and ultimately regulates cell survival or functionality depending on the cell type and the context. Notably, TRAF2 and TRAF5 can also modulate signaling by death receptors through association with TRADD, FADD or RIP1 (Table 1). Most TRAF-dependent receptors of this family trigger the canonical NF-κB pathway (RelA/p50, NF-κB1). In contrast, the alternative NF-κB pathway (RelB/p52, NF-κB2) is activated by a subset of TNF-Rs, including CD40, BAFF-R, the lymphotoxin-β receptor (LTβR), 4-1BB, and Fn14. Interestingly, however, unlike CD40 or BAFF-R, TWEAK-induced Fn14 signaling promotes NF-κB2 activation through a distinct mechanism that induces lysosomal degradation of cIAP1-TRAF2 in a cIAP1-dependent manner. The distinct TWEAK/Fn14 paradigm is covered in detail in a recent review by Silke and Brink.

Using CD40 and BAFF-R as examples, here I briefly summarize recent advances in understanding how TRAFs regulate the two NF-κB pathways and activation of MAPKs (Figure 2). In the absence of stimulation, TRAF3 constitutively binds to NIK (the upstream kinase of the NF-κB2 pathway) and TRAF2 (which associates with cIAP1/2). In this complex, cIAP1/2 induces K48-linked polyubiquitination of NIK, and thus targets NIK for proteasomal degradation and inhibits NF-κB2 activation. Following BAFF or CD154 stimulation, trimerized BAFF-R or CD40 recruits TRAF3, TRAF2, cIAP1/2 and MALT1 to membrane signaling rafts, releasing NIK from the TRAF3/TRAF2/cIAP1/2 complex. NIK protein is accumulated in the cytoplasm, induces the activation of IKKα and NF-κB2, and eventually up-regulates the expression of anti-apoptotic proteins of the Bcl-2 family (such as Bcl-2, Bcl-xL, and Mcl-1) to induce cell survival. In the receptor signaling complex, TRAF2 induces K63-linked polyubiquitination of cIAP1/2, which is subsequently activated to catalyze K48-linked polyubiquitination and degradation of TRAF3 and TRAF2. Following CD40 activation, many other signaling proteins (including TRAF5, TRAF6, TRAF1, Ubc13, MEKK1, TAK1 and NEMO) are also recruited to the cytoplasmic domain of the receptor, and the K63-specific ubiquitin ligase activity of TRAF2 and TRAF6 is rapidly stimulated. These proteins form several separate multiprotein signaling complexes, which result in the phosphorylation and activation of MEKK1 and TAK1. Activated MEKK1 and TAK1 and their associated protein complexes are subsequently released from the receptor into the cytoplasm to activate MAPKs and NF-κB1, which eventually mediate the effector functions of CD40. Interestingly, the releasing step of MEKK1 and TAK1 is inhibited by TRAF3 via a yet unknown mechanism, but promoted by cIAP1/2-catalyzed K48-linked polyubiquitination and proteasomal degradation of TRAF3. In response to BAFF stimulation, a signaling pathway of c-Raf-MEK-ERK-dependent phosphorylation and down-regulation of the pro-apoptotic protein Bim also contributes to B cell survival. In light of the evidence that TRAF1 mediates 4-1BB-induced ERK-dependent phosphorylation and down-regulation of Bim to promote T cell survival, it would be interesting to investigate the role of TRAF1 in BAFF-induced Bim down-regulation in B cells. Collectively, the above evidence indicates that TRAFs are critical regulators of signaling by the TNF-R superfamily.

TRAFs in TLR signaling

Toll-like receptors (TLRs), the best-studied family of PRRs, recognize conserved structures termed pathogen-associated molecular patterns (PAMPs) of diverse invading microbes, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi, protozoa, and parasites. They also detect endogenous molecules released from damaged or inflamed self-tissues, referred to as damage-associated molecular patterns (DAMPs). Upon sensing these molecules, TLR signaling induces the production of pro-inflammatory cytokines (such as TNFα, IL-1, IL-6, and IL-12), type I interferons (IFNα and IFNβ), chemokines, antimicrobial enzymes, and other inflammatory mediators. These provoke acute inflammatory responses as well as phagocytosis and autophagy, which represent the first line of innate immunity against pathogens. TLR signaling also serves to prime the subsequent adaptive immune responses by up-regulating adhesion molecules and co-stimulatory molecules (such as CD40, CD80, and CD86) on antigen presenting cells.

TLRs (TLR1, 2, 4–6, 10) that sense lipids or proteins are located on the cell membrane, while those (TLR3, 7, 8, 9) that recognize nucleic acids are resided in intracellular endosomes. Each TLR consists of an ectodomain containing leucine-rich repeats (LRR) that mediate sensing of PAMPs or DAMPs, and a cytoplasmic Toll/IL-1 receptor (TIR) domain that mediates downstream signal transduction. Ligand-induced TLR dimerization or oligomerization recruits TIR domain-containing adaptor proteins through TIR-TIR interactions, including MyD88, TRIF, Mal and TRAM. MyD88 is employed by all TLRs except TLR3. TRIF is only used by TLR3 and endocytosed TLR4. Mal (also known as TIRAP) facilitates the recruitment of MyD88 to TLR4, while TRAM acts as a bridging adaptor between TRIF and endocytosed TLR4. Collectively, two general pathways are used by TLRs: MyD88-dependent (all TLRs except TLR3) and TRIF-dependent (TLR3 and TLR4) pathways. Both pathways initiate complex signaling cascades of phosphorylation and ubiquitination events, which culminate in the activation of transcription factors, including NF-κB, IRFs, and AP-1 family members, leading to innate immune responses.

TRAF6 mediates both MyD88-dependent and TRIF-dependent activation of NF-κB and AP-1 (Figure 3). In MyD88-dependent TLR signaling, TRAF6 is recruited to MyD88-activated IRAK1/2, and oligomerization of TRAF6 stimulates its E3 ubiquitin ligase activity. In coordination with the E2 complex Uev1A:Ubc13, TRAF6 catalyzes the attachment of K63-linked polyubiquitin chains onto its substrates, including itself and NEMO, and synthesis of free, unanchored K63-polyubiquitin chains. Ubiquitinated TRAF6 serves as a signaling scaffold to recruit TAK1 via TAB2/3. TRAF6-generated free K63-polyubiquitin chains also bind to TAB2/3 to activate TAK1, and bind to NEMO to activate IKKα/β in the receptor complex. This ultimately results in MyD88-dependent activation of NF-κB. The TAK1 signaling complex, including TRAF6-TAB2/3-TAB1-TAK1, is subsequently dissociated from the receptor and released into the cytosol, where TAK1 activates MAPK cascades, leading to activation of AP-1. Similar to CD40 signaling, the release of the TAK1 signaling complex from TLR4 is inhibited by TRAF3, which is recruited to TLR4 by MyD88 and IRAK1. However, TRAF6 catalyzes K63-linked polyubiquitination of cIAP1/2, which is also recruited by MyD88 and IRAK1. Activated cIAP1/2 promotes K48-linked polyubiquitination and degradation of TRAF3, allowing activation of MAPKs. In TRIF-dependent TLR signaling, TRIF directly recruits TRAF6 and RIP1, which work cooperatively to activate TAK1, eventually leading to activation of NF-κB and AP-1. Interestingly, in response to engagement of TLR1, 2 or 4, TRAF6 is also translocated to mitochondria, where it ubiquitinates evolutionarily conserved signaling intermediate in Toll pathways (ECSIT), resulting in increased reactive oxygen species (ROS) generation and bacteria killing. Notably, TRAF6 is also necessary for IRF7 activation and type I IFN production induced by TLR7 and TLR9 in plasmacytoid dendritic cells (pDCs).

TRAF3 is required for both MyD88-dependent and TRIF-dependent activation of IRF3 and IRF7, and thus production of type I IFNs, a class of cytokines with potent antiviral and antibacterial activities. In MyD88-dependent signaling downstream of TLR7 and TLR9, TRAF3 is recruited to MyD88 and IRAK1. Activated TRAF3 catalyzes its K63-linked auto-ubiquitination, and assembles a signaling complex with MyD88, IRAK4, IRAK1, IKKα and IRF7. Within this complex, IRF7 is phosphorylated and activated by IRAK1 and IKKα to induce the production of type I IFNs. In TRIF-dependent signaling downstream of TLR3 and TLR4, TRAF3 interacts with oligomerized TRIF, and activated TRAF3 recruits TBK1 and IKKϵ through NAP1 and TANK. In this signaling complex, TRAF3, in cooperation with Ubc13 and/or Ubc5, catalyzes K63-polyubiquitination of TRAF3 itself, TBK1 and IKKϵ, which facilitates the phosphorylation of IRF3 and IRF7. The phosphorylated IRF3 and IRF7, in turn, form homodimers or heterodimers, translocate into the nucleus and induce the expression of type I IFNs as well as IFN-inducible gene (Figure 3).

Interestingly, TRAF1 was also identified as a TRIF-interacting protein in yeast two-hybrid screens. Overexpression of TRAF1 inhibits TRIF- and TLR3-mediated activation of NF-κB and expression of IFN-β, suggesting that TRAF1 inhibits TRIF-dependent signaling. Similarly, TRAF4 physically interacts with and functionally counteracts TRAF6 and TRIF in TLR signaling. Taken together, recent advances indicate that TRAF6, TRAF3, TRAF1 and TRAF4 play critical and largely distinct roles in signaling by TLRs.

TRAFs in NLR signaling

NOD-like receptors (NLRs) are a family of cytosolic sensors of PAMPs and DAMPs, and are functionally analogous to TLRs. Each NLR appears to be activated by multiple agonists. However, in many cases, evidence of direct interaction between NLRs and PAMPs/DAMPs is lacking. Effector functions of NLRs include secretion of pro-inflammatory cytokines, chemokines, anti-microbial peptides and type I IFNs, generation of ROS, autophagy, antigen processing, and expression of MHC class II on antigen presenting cells. These responses induce innate immune clearance of the pathogen, and also tailor the adaptive immune system to fight the infection. NLRs are characterized by a central NOD domain that mediates nucleotide-binding and oligomerization, and the C-terminal LRRs that possibly mediate ligand detection. In addition, they contain N-terminal effector domains, such as caspase recruitment domains (CARD), pyrin domains (PYD), baculovirus inhibitor of apoptosis repeat (BIR) domains, or an acidic transactivation domain, which recruit downstream signal transduction molecules after ligand sensing. One well-studied pathway of several NLRs, including NLRP3, NLRP1, NLRP6, and NLRC4, is the assembly of multi-protein complexes called ‘inflammasomes’, which contain caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC). Inflammasomes induce proteolytic processing of pro-IL-1β and pro-IL-18 into secretable IL-1β and IL-18, as well as caspase 1-dependent apoptosis termed ‘pyroptosis’. The role of TRAF2 in inflammasome signaling has recently been explored, but the published data are contradictory. Labbe et al. reported that depletion of TRAF2 by siRNA inhibits inflammasome signaling in HEK293T cells. However, Vince et al. found that inflammasome activation is normal in TRAF2−/− bone marrow-derived macrophages (BMDMs). Potential involvement of other TRAFs in inflammasome signaling remains to be elucidated.

TRAF2, TRAF5, and TRAF6 are required for NF-κB and MAPK activation induced by NOD1 and NOD2 (Figure 4), the founding members of the NLR family. Upon detection of meso-diaminopimelic acid (DAP) by NOD1 or muramyl dipeptide (MDP) by NOD2 at the vicinity of plasma membranes, oligomerization of NOD1 or NOD2 recruits the dual specificity kinase RIP2 (also called RICK) via a homotypic CARD-CARD interactions. Activated RIP2 induces the formation of the signaling complex containing TRAF2, TRAF5, TRAF6, TRAF4, CARD9, cIAP1/2, and Ubc13/Uev1A. In this complex, cIAP1/2, in coordination with Ubc13/Uev1A, catalyze K63-linked polyubiquitination of RIP2, which further recruits TAB2/3-TAB1-TAK1 and NEMO-IKKα/β, leading to NF-κB activation. Interestingly, a recent study by Damgaard et al. demonstrated that XIAP is also recruited to the NOD2 signaling complex, in which XIAP primarily conjugates ubiquitin chains on RIP2 that are linked through lysine residues other than K63 and K48. Thus, XIAP, together with cIAP1/2, constitutes the major ubiquitin ligase activity that ubiquitinates RIP2 in NOD2 signaling, and cIAP1/2 appear to be rate limiting only when XIAP is not present. It has been shown that TRAF2 and TRAF5 are required for NOD-induced NF-κB activation, while TRAF6, CARD9, and ITCH are important for p38 and JNK activation in NOD signaling. However, the exact mechanism of how these occur is still unknown. Interestingly, TRAF4 is identified as a key negative regulator of NOD2 signaling. TRAF4 binds directly to NOD2 in an agonist-dependent manner, and inhibits NOD2-induced NF-κB activation and bacterial killing. This inhibitory effect of TRAF4 requires its phosphorylation at Ser426 by IKKα, which is also recruited to the NOD2 signaling complex.

TRAF3 mediates type I IFN production induced by NOD1, and presumably also that induced by NOD2 (Figure 4). NOD1 and NOD2 induce type I IFN production through distinct mechanisms. Upon sensing DAP, oligomerization of NOD1 recruits TRAF3 via RIP2. TRAF3 in turn activates TBK1 and IKKϵ, leading to subsequent activation of IRF7 and type I IFN production in epithelial cells. In contrast, NOD2 induces type I IFN production only in response to viral ssRNA, but not in response to MDP, via a RIP2-independent pathway. Following the detection of viral ssRNA, NOD2 engages a signaling complex containing MAVS on mitochondria, which induces IRF3 activation and type I IFN production. TRAF3 has been shown to directly interact with MAVS to mediate RLR-induced type I IFN production. It is thus speculated that TRAF3 may similarly activate TBK1 and IKKϵ in NOD2-MAVS signaling, but this awaits experimental investigation.

Interestingly, TRAF3 and TRAF6 are involved in the cross-talk between several NLRs and TLRs or RLRs. TRAF3 regulates NLRP12-mediated suppression of TLR-driven NF-κB activation, as NLRP12 interacts with both NIK and TRAF3. TRAF6 interacts with NLRX1, which negatively regulates NF-κB activation induced by RIG-I or TLR4. Similarly, NLRC3 also inhibits TLR-induced NF-κB activation by interacting with TRAF6 and reducing K63-linked polyubiquitination of TRAF6.

TRAFs in RLR signaling

RIG-I like receptors (RLRs), including RIG-I, MDA5, and LGP2, are a family of cytosolic RNA helicases that detect viral RNA PAMPs accumulated during viral infection or replication. RLRs are indispensable for antiviral responses in most cell types except pDCs. RIG-I/MDA5 signaling rapidly elicits the production of type I and type III IFNs and proinflammatory cytokines. RIG-I and MDA5 exhibit different ligand specificity and respond to different viruses, whereas LGP2 facilitates or antagonizes recognition of viral RNA by MDA5 and RIG-I. RLRs are structurally characterized by a central DExD/H box RNA helicase domain involved in RNA binding and ATPase function, and a carboxyl-terminal domain (CTD) that contains a positively charged RNA binding pocket. RIG-I and MDA5, but not LGP2, also possess two N-terminal CARDs that are required to trigger downstream signaling. Upon detection of RNA PAMPs, RIG-I/MDA-5 undergoes conformational change that leads to dimerization and association with the mitochondrial antiviral signaling adaptor (MAVS, also called IPS-1, VISA, or Cardif) through homotypic CARD-CARD interactions. MAVS consists of an N-terminal CARD domain, a central proline-rich region (PRR), several TRAF-interacting motifs, and a C-terminal transmembrane domain, which anchors the protein on the outer membranes of mitochondria. Dimerization of MAVS directly recruits TRAF2, TRAF3, TRAF5, TRAF6, CARD9 and TRADD, which serve as a platform to assemble signaling complexes at mitochondrial outer membranes. These signaling complexes contain players that are further recruited by TRAFs or TRADD, including cIAP1/2, TANK-NAP1-SINTBAD, TBK1-IKKϵ, NEMO, IKKα/IKKβ, TAB2/3-TAB1-TAK1, MEKK1, Bcl10, and RIP1-FADD-Casp8-Casp10. RIG-I/MDA5 signaling cascades culminate in the phosphorylation and activation of IRF3, IRF7, NF-κB and AP-1, which work cooperatively to induce the expression of IFNs and proinflammatory cytokines (Figure 5).

TRAF3 is essential for RLR-induced IRF3 but not NF-κB activation, and TRAF3 deficiency results in impaired type I IFN induction in response to RNA virus infection. MAVS has a TRAF3-interacting motif in the C-terminus that is verified by crystallography, and Tyr9 phosphorylation on MAVS also facilitates the recruitment of TRAF3. Additionally, TRAF3-MAVS interaction requires the assistance of another TRAF3-interacting protein, UXT-V1. Following its recruitment to MAVS and in conjunction with Ubc5, TRAF3 undergoes K63-linked auto-ubiquitination, which enhances its ability to bind to NEMO and TANK-NAP1-SINTBAD, thus allowing the recruitment and activation of TBK1 and IKKϵ. Interestingly, a recent study shows that linear ubiquitination of NEMO switches it from a positive to a negative regulator of RIG-I signaling, as linear ubiquitinated NEMO associates with TRAF3 but disrupts the MAVS-TRAF3 complex. The NEMO-like adaptor proteins TANK, NAP1, and SINTBAD are constitutively bound to both TBK1 and IKKϵ. Autoubiquitinated TRAF3 activates TBK1 and IKKϵ to induce the phosphorylation, dimerization and nuclear translocation of IRF3, which triggers the production of type I IFNs.

Depletion of either TRAF2 or TRAF5 leads to reduced IRF3 and NF-κB activation upon RIG-I stimulation, and TRAF2 and TAK1 are important for p38 activation. Biochemical studies revealed TRAF2 and TRAF5 interaction motifs in the C-terminal region of MAVS. Upon RIG-I signaling, interaction of TRAF5 with MAVS induces K63-linked TRAF5 auto-ubiquitination and subsequent NEMO-dependent activation of IRF3 and NF-κB. Similarly, activation of p38 by RIG-I proceeds via a TRAF2-TAK1-dependent pathway. The p38 activation in turn stimulates the production of IFNs and IL-12. Nonetheless, details of TRAF2- or TRAF5- signaling pathways downstream of MAVS remain to be elucidated.

TRAF6 is required for RLR-induced IRF7 activation and also contributes to activation of NF-κB, JNK, and p38 by directly interacting with MAVS, which has two TRAF6-interacting motifs. Activation of IRF7 after viral infection resembles IRF3 activation, and involves the direct phosphorylation of IRF7 by TBK1 and IKKϵ. However, activation of IRF7 but not IRF3 is impaired in TRAF6−/− fibroblasts, and TRAF6 mediates IRF7 ubiquitination. Thus, MAVS-induced IRF7 activation is transduced through a unique TRAF6-dependent pathway. Uncoupling IRF3 from the IRF7 activation pathway might be a way of avoiding their simultaneous inhibition by virus-encoded inhibitory proteins. TRAF6 and MEKK1 are also important for RLR-induced activation of NF-κB and MAPKs. Interestingly, RIG-I-MAVS-TRAF6 signaling leads to IKKβ-mediated phosphorylation of p65 at ser536, which is under the control of the NADPH oxidase NOX2.

Notably, cIAP1 and cIAP2 are also recruited to MAVS, and mediate K48- and K63- linked polyubiquitination of TRAF3 and TRAF6 in response to viral infections. However, the kinetics of these two types of ubiquitination on TRAF3 and TRAF6 is still unclear. Interestingly, viruses also induce IRF3-dependent apoptosis in infected cells, which require the presence of RIG-I, MAVS, TRAF3, TRAF2, TRAF6 and TBK1, as demonstrated by studies using genetically defective mouse and human cell lines. Apoptosis is triggered by direct interaction of IRF3, through a newly identified BH3 domain, with the pro-apoptotic protein Bax. Co-translocation of IRF3 and Bax to mitochondria results in the induction of mitochondria-dependent apoptosis, and transcriptionally inactive IRF3 mutants could efficiently mediate apoptosis. Although why TRAF3, TRAF2 and TRAF6 are all required for IRF3-induced apoptosis awaits further clarification, it appears that these TRAF molecules cooperate in this process.

TRAFs in cytokine receptor signaling

It was initially recognized that TRAF6 is utilized for signaling by the IL-1R family (IL-1R, IL-18R and IL-33R), which also contain TIR domains found in TLRs. However, recent evidence indicates that TRAFs also directly regulate signaling by a variety of other cytokine receptors, including receptors for the proinflammatory IL-17 family, anti-viral IFNs, anti-inflammatory TGFβ, and the T cell cytokine IL-2.

IL-17 receptors

The IL-17 family are important in host defense against bacterial, fungal and helminthic parasite infections. The founding member of this family, IL-17, is the defining cytokine of a new T helper cell population termed “Th17”, which contributes significantly to the pathogenesis of multiple autoimmune and inflammatory diseases. Signature target genes of IL-17 include chemokines, proinflammatory cytokines, inflammatory mediators, anti-microbial peptide, and matrix metalloproteases (MMPs). IL-17 (A/F) signals through a heteromeric receptor complex formed by IL-17RA and IL-17RC. IL-17Rs have two extracellular fibronectin III-like domains and a cytoplasmic SEF/IL-17R (SEFIR) domain. Ligand-induced association of IL-17RA and IL-17RC recruits a novel adaptor protein Act1 through SEFIR domain-mediated homotypic interaction. Act1 is a U-box E3 ubiquitin ligase that contains both a SEFIR domain and TIMs, and further recruits TRAF6, TRAF2 and TRAF5. In cooperation with Ubc13/Uev1A, Act1 catalyzes K63-linked polyubiquitination of TRAF6, which in turn mediates the ubiquitination of IL-17RA and induces the activation of NF-κB through TAK1 and IKKs. Activated NF-κB further induces the expression of IkBζ, C/EBPδ and C/EBPβ, transcription factors that work in concert with NF-κB to induce the expression of signature target genes of IL-17. On the other hand, TRAF6 also induces GSK3β activation likely through PI-3K, and ERK1/2 activation likely through Raf1. Activated GSK3β and ERK induce dual phosphorylation of C/EBPβ and thereby inhibit its activity. Thus, TRAF6 is essential for IL-17 signaling (Figure 6).

Interestingly, TRAF2 and TRAF5 transduce the IL-17 signals to stabilize mRNA transcripts of chemokines (such as CXCL1) and cytokines (such as IL-6) by recruiting the splicing factor SF2 (also known as alternative splicing factor, ASF) into the IL-17R-Act1 signaling complex. The IL-17R-Act1-TRAF2-TRAF5 complex also induces the activation of MAPKs, which further enhance mRNA stability. Notably, formation of this complex requires IKKϵ, an inducible IKK that mediates Act1 phosphorylation at Ser311, adjacent to a putative TRAF-binding motif. Substitution of Ser311 of Act1 with alanine impairs the IL-17-induced Act1-TRAF2-TRAF5 interaction and inflammatory gene expression. In contrast, TRAF3 and TRAF4 are negative regulators of IL-17R signaling. Upon IL-17 stimulation, IL-17RA and IL-17RC directly recruit TRAF3 via a distal C-terminal TRAF3-binding site. The binding of TRAF3 to IL-17Rs interferes with the formation of the activation signaling complex of IL-17R-Act1-TRAF6, resulting in suppression of downstream signaling, including NF-κB and MAPK activation, and production of inflammatory cytokines and chemokines. TRAF4 exerts its negative regulation on IL-17 signaling by competing with TRAF6 for the interaction with Act1, as TRAF4 and TRAF6 use the same TIMs on Act1. Indeed, primary epithelial cells derived from TRAF4−/− mice display markedly enhanced IL-17 signaling. Thus, both TRAF3 and TRAF4 restrict IL-17 signaling at receptor proximal steps (Figure 6).

IFN receptors

Interferons induce the synthesis of a variety of antiviral proteins that mediate swift innate immune responses to control virus replication and spread, and also shape the adaptive immune response by acting directly on T and B cells. TRAF2 and TRAF6 are recognized as direct signal transducers of IFN receptors. Upon IFN engagement, TRAF2 directly binds to the membrane proximal half of the signal-transducing subunit of the IFN receptor, IFNAR1, and is required for IFN-induced NF-κB2 activation and anti-viral responses. Similarly, direct interaction of TRAF6 with the intracellular domain of IFNλR1 regulates NF-κB activation and IFNλR1 stability in response to type III IFNs (IFNλ1, IFNλ2, and IFNλ3). Whether other TRAFs contribute to the regulation of IFN signaling remains to be determined.

TGFβ receptors

The anti-inflammatory cytokine TGFβ binds to type II and type I serine/threonine kinase receptors (TβRII and TβRI). TRAF6 interacts with a consensus TIM present in TβRI. The TβRI-TRAF6 interaction induces auto-ubiquitination of TRAF6. TβRI kinase activity is required for activation of the canonical Smad pathway, whereas TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Activated TRAF6 mediates K63-linked polyubiquitylation of TAK1 at Lys34 and Lys158, and results in subsequent activation of p38 and JNK, leading to cell apoptosis. Thus, TRAF6 is specifically required for the Smad-independent activation of JNK and p38 in response to TGFβ. However, in cancer cells, TRAF6-mediated K63-linked polyubiquitination of TβRI also promotes cleavage of TβRI by TNFα converting enzyme (TACE) in a PKCζ-dependent manner. The liberated intracellular domain of TβRI associates with the transcriptional regulator p300 to activate genes involved in tumor invasiveness, such as Snail and MMP2. In this case, TRAF6 is critical for TGFβ-induced invasion of cancer cells. Additionally, TRAF6 mediates the suppressive effect of IL-1β or LPS on TGFβ-induced signaling through interaction with the type III TGF-β receptor (TβRIII), an accessory receptor that presents the TGFβ ligand to TβRII. Co-treatment with TGFβ and IL-1β or LPS promotes the interaction between phosphorylated TβRIII and ubiquitinated TRAF6, and thereby sequesters TβRIII from the TβRII/TβRI complex, resulting in inhibition of Smad2/3 activation. Taken together, TRAF6 plays multiple roles in signaling by TGFβ receptors. Interestingly, TGFβ also induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels in T cells. No evidence is available about the participation of other TRAFs in TGFβ signaling.

IL-2 receptor

The binding of TRAF6 to the TIM of the IL-2R β-chain negatively regulates IL-2-induced Jak1 activation in CD4 T cells, which is likely involved in the proper regulation of T cell activation and development.

T cell receptor

TRAF1, TRAF3, and TRAF6 are able to regulate signaling by the T cell receptor (TCR). TRAF1 inhibits CD3-induced NF-κB2 activation and proliferation in T cells. TRAF3 is recruited to the signaling rafts, and mediates the synergistic activation of ERK, LAT, PLCγ1 and ZAP70 as well as cytokine production and proliferation in T cells following co-stimulation with TCR and CD28. TRAF6 is also recruited to the TCR signaling rafts containing CARMA1-MALT1-Bcl10-PKCθ-IKK-Caspase 8 via interaction with the paracaspase MALT1, and contributes to the induction of NF-κB activation and IL-2 production in T cells. Interestingly, a recent study by Xie et al has shown a distinct mechanism of TRAF6 in TCR signaling, in which TRAF6 is recruited to the TCR/CD28 signaling complex by LAT and promotes the ubiquitination and phosphorylation of LAT as well as the activation of NF-AT in T cells.

C-type lectin receptors

Using macrophages derived from TRAF6−/− mice, it has been shown that TRAF6 is required for NF-κB and JNK activation, and expression of proinflammatory cytokines in response to engagement of C-type lectin receptors during fungal infection. This will elicit further studies of other TRAFs in signaling by C-type lectin receptors.

DNA damage response

TRAF6 is essential for DNA damage-induced NF-κB activation. In this process, TRAF6 is activated by the kinase ataxia telangiectasia mutated (ATM), which is a DNA strand break sensor. Following DNA damage, ATM translocates in a calcium-dependent manner to cytosol and membrane fractions, and interacts with TRAF6 via a TIM, resulting in K63-linked polyubiquitination of TRAF6 and recruitment of cIAP1. The ATM-TRAF6-cIAP1 module stimulates TAB2-dependent TAK1 phosphorylation, and cIAP1 catalyzes monoubiquitination of NEMO at Lys285. NEMO monoubiquitination is a prerequisite for genotoxic NF-κB activation and DNA damage response. Potential involvement of other TRAFs in this response awaits further investigation.

Substrates, E3 ligases and deubiquitinases of TRAFs

Ubiquitination has emerged as a key regulatory mechanism of TRAFs in signaling. As mentioned above in receptor signaling sections, E3 ligase activity has been demonstrated for TRAF2, TRAF3, TRAF5 and TRAF6, which catalyze non-degradative K63-linked polyubiquitination of their substrates. This is mediated in cooperation with the E2 ubiquitin-conjugating enzymes Ubc13-Uev1A or UbcH5c. It is believed that K63-linked polyubiquitin chains serve as docking sites for formation of signaling complexes, facilitate the recruitment and activation of effector kinases, and thus enable the propagation of signals. The substrates of TRAFs include TRAF themselves, receptors, kinases, adaptor proteins, transcription factors, E3 ubiquitin ligases, and other functional proteins involved in autophagy or ROS production (Table 2). However, in many cases, substrates of TRAFs (especially those of TRAF2, TRAF3 and TRAF5) have not been unequivocally demonstrated by in vitro ubiquitination assays using purified proteins. Interestingly, a recent study has shown that TRAF2 becomes a highly active K63-specific ubiquitin ligase when bound to sphingosine-1-phosphate (S1P), which appears to be a cofactor for TRAF2 E3 ligase activity. This suggests that addition of S1P may improve the efficiency of in vitro ubiquitination assays for TRAF2. Future studies need to determine whether similar cofactors exist for TRAF3 and TRAF5. Interestingly, however, the crystal structure of the RING domain of TRAF2 and the phenotype of the ΔRING TRAF2 mutant suggest that TRAF2 may not function as an E3 ligase at all. The controversy about whether TRAF2 is actually a RING E3 ligase is described in detail in an excellent review by Silke.

While serving as E3 ligases themselves, TRAFs are also substrates of other E3 ligases that catalyze K63-linked or K48-linked polyubiquitination (Table 3). K63-linked polyubiquitination of TRAFs usually leads to protein-protein interactions and promotes signal transduction. For example, Act1-mediated K63-linked ubiquitination of TRAF6 recruits TAB2/3-TAK1 and NEMO to activate NF-κB in IL-17R signaling, while cIAP1/2-catalyzed K63-linked ubiquitination of TRAF3 recruits TBK1 and IKKϵ to induce type I IFN production in RIG-I signaling. In an exceptional case, Pellino3-induced ubiquitination of TRAF6 at Lys124 suppresses the ability of TRAF6 to interact with and ubiquitinate IRF7, and thus inhibits type I IFN production in TLR3 signaling. In contrast, K48-linked polyubiquitination of TRAFs results in degradation of TRAF proteins by the 26S proteasome. K48-linked E3 ligases of TRAFs include cIAP1/2, Triad3A, AWP1, SOCS2, Siva-1, Numbl and CHIP. For example, upon viral infection, Triad3A is up-regulated, and induces K48-linked ubiquitination and degradation of TRAF3, thereby forming a negative feedback loop to halt RIG-I signaling and type I IFN production. Thus, K48-linked ubiquitination and subsequent degradation of TRAFs serve as a negative regulatory mechanism of TRAF-dependent signaling.

A second negative regulatory mechanism of TRAFs is provided by deubiquitinases that cleave K63-linked polyubiquitin chains from TRAFs, which is just beginning to be understood. The known deubiquitinating enzymes (DUBs) of TRAFs include: (1) ubiquitin-specific proteases, such as CYLD, USP2a, USP4, USP20 and USP25; (2) ovarian tumor (OTU) domain-containing DUBs, such as DUBA (also known as OTUD5), OTUB1, OTUB2, and A20; (3) a novel DUB named monocyte chemotactic protein-induced protein 1 (MCPIP1) (Table 4). CYLD, a tumor suppressor and a target gene of NF-κB, negatively regulates NF-κB and JNK activation by removing K63-linked polyubiquitin chains from TRAF2 and TRAF6 as well as several other signaling proteins. Expression of DUBA is up-regulated in TLR and IL-1R stimulated cells. DUBA specifically targets and de-conjugates the K63-linked polyubiquitin chains from TRAF3, resulting in TBK1-IKKϵ dissociation from TRAF3 and inhibition of type I IFN production induced by TLRs and RLRs. However, DUBA does not affect NF-κB2 activation, which is entirely dependent on K48-linked degradative ubiquitination of TRAF3. Interestingly, A20, an unusual enzyme that contains both ubiquitinating and deubiquitinating activities, negatively regulates inflammation by inhibiting NF-κB activation in TNF-R and TLR signaling. A20 is a target gene of NF-κB, and able to remove K63-linked polyubiquitin chains from TRAF6 to turn off NF-κB activation. A20 also inhibits the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by promoting K48-linked polyubiquitination and degradation of the E2 enzymes Ubc13 and UbcH5c. Furthermore, A20 is capable of targeting an associated signaling molecule such as TRAF2 to the lysosomes for degradation, a process that does not require A20 ubiquitin modifying activity. Notably, A20−/− and MCPIP1−/− mice spontaneously develop severe inflammatory syndrome, while CYLD−/− and Usp25−/− mice are more susceptible to inflammation. Thus, negative regulation of TRAF signaling is necessary to prevent harmful immune responses and inflammatory diseases.

In addition to ubiquitination, other post-translational modifications, including phosphorylation and glutathionylation, are also reported to regulate TRAFs in signaling. Phosphorylation of TRAF1 (at Ser 139 in mouse and Ser 146 in human by PKN1) inhibits TNF-R2-dependent tonic NF-κB and JNK signaling in HeLa cells, and also has a negative impact on the recruitment of TBK1 to the 4-1BB signaling complex and the subsequent NF-κB activation in T cells. Phosphorylation of TRAF2 (at Ser11 and Ser55 by PKCζ or IKKϵ, and at Thr117 by PKCδ and PKCϵ), which promotes K63-linked ubiquitination of TRAF2 and NF-κB activation, has been demonstrated in TNFα signaling or in transformed cells. Following NOD2 activation, phosphorylation of TRAF4 (at Ser 426 by IKKα) negatively regulates NOD2 signaling in macrophages, including NF-κB activation, cytokine production and antibacterial activity. Tyrosine phosphorylation of TRAF6 by Fyn and c-Src has been shown following LPS stimulation. Interestingly, a recent study reported that TRAF6 is S-glutathionylated under normal conditions. Upon IL-1 stimulation, TRAF6 undergoes deglutathionylation catalyzed by glutaredoxin-1 (GRX-1), a process that is essential for TRAF6 auto-ubiquitination and subsequent NF-κB activation. These findings suggest that different post-translational modifications of TRAF proteins coordinate to regulate the activity of TRAFs in signaling in a dynamic manner.

Viral proteins that target or hijack TRAFs

TRAFs are critical players in host immunity, as demonstrated by their shared usage by both innate immune receptors (such as TLRs, NLRs, RLRs, and cytokine receptors) and adaptive immune receptors (such as CD40, BAFF-R, OX40, 4-1BB, and TCR). Interestingly, viruses and bacteria have developed a variety of strategies to target or hijack TRAFs to evade host immune responses and to promote their own propagation or persistence (Table 5). (1) Several viral and bacterial proteins can function as DUBs to deubiquitinate TRAFs and thus inhibit type I IFN production in RIG-I or TLR signaling. Examples include Lb(pro) of foot-and-mouth disease virus, X protein (HBx) of hepatitis B virus, and YopJ of the Gram- bacterium Yersinia pestis. (2) Some viral proteins can specifically interact with TRAFs and disrupt the formation of TRAF signaling complexes. For example, Gn protein of NY-1 hantavirus and M protein of severe acute respiratory syndrome (SARS) coronavirus disrupt or prevent the formation of TRAF3-TBK1-IKKϵ complex to inhibit type I IFN production. Similarly, A52R and K7 proteins of vaccinia virus disrupt signaling complexes containing TRAF6 and IRAK2 to block NF-κB activation and antiviral defense. (3) Some viral proteins usurp TRAFs for viral signaling to promote their own propagation or persistence. The best example of this group is latent membrane protein 1 (LMP1) of Epstein-Barr virus, which sequesters most cellular TRAF3, and hijacks TRAF1, 2, 3, 5 and 6 to mimic constitutively activated CD40 signaling. (4) The v-FLIP member MC159 of the human molluscum contagiosum virus mediates the recruitment of both TRAF2 and TRAF3 into the Fas death inducing signaling complex to modulate Fas signaling, and powerfully inhibits both caspase-dependent and caspase-independent cell death induced by Fas. (5) Some viruses up-regulate the expression of specific miRNAs to target TRAFs. For example, the Tat protein of HIV-1 and VSV infection up-regulate miR-32 and miR-146a, which directly target the protein expression of TRAF3 and TRAF6, respectively. Together, the above evidence further highlights the crucial importance of TRAFs in host immunity against pathogens.

In vivo functions of TRAFs in mice

The in vivo functions of TRAFs in whole animals have been explored by gene targeting in mice. Mice genetically deficient in individual TRAFs have been generated. Among these knockout mice, only TRAF1−/−, TRAF5−/−, and 67% of TRAF4−/− mice could survive to adulthood. In contrast, mice deficient in TRAF2, 3, or 6 exhibit perinatal death with multiple organ abnormalities, indicating that TRAF2, 3, and 6 are indispensable in early development. Although viable, mice deficient in TRAF1, 4 or 5 exhibit distinct phenotypes (Table 6). For example, skin of TRAF1−/− mice is hypersensitive to TNF-induced necrosis, and these mice are resistant to allergic lung inflammation in an experimental model of asthma. TRAF4−/− mice suffer respiratory disorder and wheezing caused by tracheal ring disruption, and exhibit numerous developmental abnormalities, including defects in the development of the axial skeleton and in the closure of the neural tube as well as myelin perturbation. For mice with early lethality, the causes of death appear to be different. TRAF2−/− mice succumb to severe colitis that result from apoptosis of colonic epithelial cells and accumulation of IL-10-secreting neutrophils, which can be ameliorated by deletion of TNFR1 or combined treatment with neutralizing antibodies against TNFα and IL-10. The early lethality of TRAF3−/− mice is rescued by compound loss of the NF-κB2 gene, suggesting that constitutive NF-κB2 activation leads to the lethal phenotype of TRAF3−/− mice. In contrast, TRAF6−/− mice die of severe osteopetrosis, splenomegaly, and thymic atrophy. Taken together, these findings demonstrate that although TRAFs have overlapping functions, each TRAF molecule also plays unique and distinct roles that could not be compensated or substituted by other TRAFs in whole animals.

During the past few years, different laboratories have employed the conditional gene targeting strategy to circumvent the early lethality of TRAF−/− mice. These new mouse models allow more detailed analyses and direct comparison of specific functions of TRAFs in different cell types of whole animals (Table 6).

B lymphocytes

TRAF2, 3, 5 and 6 are important in the survival, development, and activation of B cells. In the absence of either TRAF2 or TRAF3, B cells exhibit remarkably prolonged survival independent of BAFF, which result from the constitutive NF-κB2 activation. This is further corroborated by the evidence that deletion of cIAP1 and cIAP2 (constitutive interacting partners of TRAF2) also renders BAFF-independent survival of B cells in mice due to constitutive NF-κB2 activation. Strikingly, the development of mature B cells, including the follicular and marginal zone subpopulations of the spleen, are unimpaired in BAFF-R−/− mice that also lack B cell expression of either TRAF2, TRAF3, or cIAP1/cIAP2. Thus, the survival and maturation pathways normally activated by physiologic triggering of BAFF-R by BAFF are constitutively activated when the expression of TRAF2, TRAF3, or cIAP1/cIAP2 is absent from B cells. Vastly prolonged survival of B cells eventually leads to autoimmune manifestations and B lymphoma development in B cell-specific TRAF3−/− mice. Interestingly, TRAF3−/− B cells also display enhanced activation in response to signaling by TLR3, TLR4, TLR7, or TLR9. Gardam et al. further directly compared CD40 signaling in B cell-specific TRAF3−/−, TRAF2−/−, and cIAP1−/−cIAP2−/− mice. Interestingly, loss of TRAF2, TRAF3, or cIAP1/cIAP2 in B cells has very different impacts on CD40 signaling. TRAF3−/− B cells exhibit accelerated phosphorylation of JNK, ERK, and p38 in response to CD40 signaling. In contrast, TRAF2−/− B cells display slower and decreased CD40 signaling, while cIAP1−/−cIAP2−/− B cells show impaired CD40 signaling. Consistent with this, B cell-specific TRAF2−/− and cIAP1−/−cIAP2−/− but not TRAF3−/− mice exhibit dramatically reduced germinal center formation following immunization with sheep red blood cells. Notably, TRAF5−/− B cells show defects in proliferation and up-regulation of surface molecules in response to CD40 stimulation, and reduced production of IgM and IgG1 in response to stimulation with CD40 plus IL-4. Unexpectedly, TRAF6 ablation results in defects in generation of CD5+ B1 cells, reduced number of mature B cells in the bone marrow and spleen, and impaired T-dependent and T-independent antibody responses.

T lymphocytes

TRAFs (except TRAF4) play critical roles in regulating T cell immunity. TRAF1−/− T cells exhibit hyperproliferation and increased production of Th2 cytokines (IL-4, IL-5 and IL-13) in response to TCR signaling, but defective 4-1BB-mediated survival responses in effector and memory CD8 T cells. Hyperproliferation of TRAF1−/− T cells is due to constitutive activation of the NF-κB2 pathway. Paradoxically, TRAF2−/− or TRAF3−/− T cells display neither prolonged survival (as that observed in B cells) nor hyperproliferation (as that observed in TRAF1−/− T cells), despite their constitutive processing and activation of NF-κB2. However, the TRAF2-NIK-NFκB2 pathway does drive the development of fatal autoimmune inflammatory disorder in TRAF2−/−TNFα−/− mice. Surprisingly, T cell-specific TRAF3−/− mice have increased frequency of regulatory T (Treg) cells, and exhibit defective T-dependent IgG1 responses and T cell-mediated immunity to infection with Listeria monocytogenes, which is due to impaired TCR/CD28 signaling. Similarly, CD27-mediated co-stimulatory signaling was reduced in TRAF5−/− T cells. In contrast, TRAF6−/− mice show a severe defect in Treg development in thymus. T cell-specific deletion of TRAF6 results in the development of multiorgan inflammatory disease. TRAF6−/− T cells exhibit hyperactivation of the PI3K-Akt pathway, resistance to suppression by Treg cells, and also resistance to anergizing signals. TRAF6−/− CD4 T cells display increased Th17 differentiation, due to enhanced sensitivity to TGFβ-induced Smad2/3 activation and IL-2 down-regulation. Interestingly, activated TRAF6−/− CD8 T cells exhibit defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal, resulting in a profound defect in memory CD8 T cell development after infection.

DCs and mast cells

TRAF1, 2, 3, 4 and 6 regulate the functions of dendritic cells (DCs). Arron et al. demonstrated the cooperation of TRAF1 and TRAF2 in DCs. TRAF1-/- DCs matured in CD154 display impaired NF-κB activation and survival but increased TRAF2 degradation in response to CD154 re-stimulation. TRAF3−/− DCs produce increased amounts of IL-12 but reduced amounts of IL-10 and little type I IFN in response to TLR7 and TLR9 signaling. TRAF3−/− DCs also display constitutive NF-κB2 activation but not prolonged survival. TRAF4−/− DCs exhibit reduced migration both in transwell experiments and in vivo. Interestingly, TRAF6 is required for DC maturation and activation. In response to either microbial components or CD40L, TRAF6−/− DCs fail to up-regulate surface expression of MHC class II and CD86, or produce inflammatory cytokines. Similarly, TRAF6−/− mast cells exhibit impaired production of IL-6, CCL-9, IL-13, and TNF following FcϵRI aggregation by IgE.

Hepatocytes and skeletal muscles

Hepatocyte-specific TRAF2−/− mice exhibit significantly decreased blood glucose levels under high-fat diet conditions. Although these mice show normal insulin signaling and the hypoglycemic response to insulin, they have severely impaired glucagon signaling and the hyperglycemic response to glucagon. In addition, TRAF2 overexpression significantly increases the ability of glucagon or a cAMP analog to stimulate CREB phosphorylation, gluconeogenic gene expression, and hepatic glucose production in primary hepatocytes. Thus, hepatic cell TRAF2 autonomously promotes hepatic gluconeogenesis, and contributes to hyperglycemia in obesity. Interestingly, skeletal muscle-specific depletion of TRAF6 in mice improves satellite cell activation and skeletal muscle regeneration through up-regulation of Notch signaling and reducing the inflammatory repertoire. TRAF6 deficiency inhibits the induction of atrophy program in response to starvation, denervation, or cancer cachexia by suppressing the expression of key regulators of atrophy, including MAFBx, MuRF1, p62, LC3B, Beclin1, Atg12, and Fn14. Ablation of TRAF6 also improves the phosphorylation of Akt and FoxO3a and inhibits the activation of 5′ AMP-activated protein kinase in skeletal muscle in response to starvation. Moreover, K63-linked autoubiquitination of TRAF6 regulates ER stress and unfolding protein response pathways in starvation-induced muscle atrophy. It remains to be elucidated whether other TRAFs regulate hepatocyte and skeletal muscle functions.

Atherosclerosis

Experiments of mouse models of atherosclerosis have provided evidence that TRAF1, 5 and 6 regulate the pathogenesis of this disease. Missiou et al. reported that TRAF1 deficiency attenuates atherosclerosis in low-density lipoprotein receptor (LDLR)−/− mice by impairing monocyte recruitment to the vessel wall. Deletion of TRAF1 inhibits adhesion of inflammatory cells to the endothelium, reduces the expression of CD29 in macrophages, and decreases the expression of the adhesion molecules ICAM-1 and VCAM-1 in endothelial cells. In contrast, TRAF5 deficiency accelerates atherogenesis in LDLR−/− mice. Deletion of TRAF5 in endothelial cells or in leukocytes enhances adhesion of inflammatory cells to the endothelium, thus facilitating inflammatory cell recruitment to the atherosclerotic plaques. In addition, TRAF5 deficiency increases the expression of adhesion molecules and chemokines, and potentiates macrophage lipid uptake and foam cell formation. Interestingly, endothelial and myeloid cell TRAF6 proteins have opposite roles in atherosclerosis in ApoE−/− mice. Endothelial TRAF6 deficiency inhibits atherosclerosis by reducing proinflammatory gene expression and monocyte adhesion to endothelial cells. In contrast, myeloid cell-specific TRAF6 deletion exacerbates atherosclerosis. TRAF6−/− macrophages exhibit impaired expression of the atheroprotective cytokine IL-10, elevated ER stress, increased sensitivity to oxidized LDL-induced apoptosis, and reduced capacity to clear apoptotic cells. Similar mouse models of TRAF2, 3 and 4 need to be generated and characterized in future studies.

TRAFs in human diseases

Findings obtained from TRAF-deficient mouse models have laid the basis to understand the roles of TRAFs in the pathogenesis of human diseases. Given their importance in regulating the development, survival and activation of various cell types, it would be expected that aberrant functions of TRAFs may contribute to different diseases. However, the roles of TRAFs in human diseases are just beginning to be revealed. Available evidence implicates TRAFs in the pathogenesis of cancers, autoimmune diseases, immunodeficiencies, and neurodegenerative diseases (Table 7).

B cell malignancies

Growing literature documents the prominent relevance of TRAF3, TRAF2 and TRAF1 in B cell malignancies. As predicted from their critical roles in inhibiting B cell survival, biallelic deletions or inactivating mutations of TRAF3 and TRAF2 frequently occur in primary human samples of B cell neoplasms. Deletions and mutations of TRAF3 have been reported in multiple myeloma, Waldenström’s macroglobulinemia, Hodgkin lymphomas (HLs), and a variety of non-Hodgkin lymphomas (NHLs), including splenic marginal zone lymphoma, B cell chronic lymphocytic leukemia (B-CLL), and mantle cell lymphoma. Similarly, inactivating mutations of TRAF2 have been identified in multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Single nucleotide polymorphisms (SNPs) of TRAF3 are also associated with altered risk of multiple myeloma. In contrast, TRAF1 expression is ubiquitously elevated in both HLs and NHLs, especially in CLL and mediastinal large B-cell lymphoma. In addition, TRAF1 SNPs are associated with NHLs. Thus, TRAF3 and TRAF2 are tumor suppressive, whereas TRAF1 appears to be oncogenic in B cells.

Carcinomas

Overexpression and gene amplification of TRAF4 and TRAF6 have been reported in human carcinomas. TRAF4 is overexpressed in breast and lung carcinomas. TRAF4 protein overexpression is limited to cancer cells and the subcellular localization is consistently cytoplasmic in a large majority of cases. Increased TRAF4 gene copy number is one major mechanism responsible for TRAF4 protein overexpression in human cancers. Indeed, TRAF4 is located at chromosome 17q11.2 in a region of amplification devoid of other known oncogenes. Intriguingly, TRAF4 is a target gene of the p53 family of transcription factors, including p63, p73 and p53, in squamous cell carcinoma of the head and neck (SCCHN). TRAF4 locates in the nucleus in normal oral epithelium and highly/moderately differentiated cells, but is localized in the cytoplasm in poorly differentiated SCCHN. Overexpression of TRAF4 in SCCHN induces apoptosis and suppresses colony formation. Thus, TRAF4 overexpression has different outcomes in different carcinomas. Notably, TRAF6 gene is located in another frequently amplified region at chromosome 11p13. TRAF6 exhibits overexpression and gene amplification in lung cancer and osteosarcoma cells. Downregulation of TRAF6 in human lung cancer and osteosarcoma cells suppresses NF-κB activation, cell survival and proliferation, and tumor formation and invasion. These observations suggest that TRAF6 overexpression may promote the tumorigenesis and invasion of lung cancer and osteosarcoma cells.

Autoimmune diseases

Single nucleotide polymorphisms (SNPs) in TRAFs have been linked to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). SNPs of TRAF6 are associated with both SLE and RA. Similarly, SNPs at the TRAF1/C5 locus are associated with both SLE and RA. A single SNP (rs7514863), mapping upstream of the TRAF5 gene and affecting a putative transcription factor binding site, demonstrates a significant association with RA. In addition, decreased expression of TRAF2 has been detected in peripheral blood mononuclear cells of SLE patients. However, further association and functional studies are required to determine whether these TRAFs play causal roles in increasing susceptibility to SLE or RA.

Immunodeficiencies

An autosomal dominant mutation of TRAF3 has been reported in a young adult with a history of herpes simplex virus-1 (HSV-1) encephalitis in childhood. The TRAF3 mutant allele is loss-of-expression, loss-of-function, dominant-negative, and associated with impaired responses upon stimulation of both TNF-Rs and TLRs. The recurrent HSV-1 infection and encephalitis result from the impairment of TLR3-induced type I IFN production.

Hypohidrotic ectodermal dysplasia

A heterozygous mutation of TRAF6 has recently been identified in a patient with hypohidrotic ectodermal dysplasia (HED). The mutant TRAF6 protein is capable of forming a complex with TAK1 and TAB2, but cannot bind to the receptor XEDAR. Furthermore, the mutant TRAF6 protein potently inhibits the interaction between wild type TRAF6 and XEDAR, and suppresses the XEDAR-mediated NF-κB activation. Thus, this mutant TRAF6 protein acts in a dominant-negative manner to affect the XEDAR-mediated NF-κB activation during the development of ectoderm-derived organs, leading to HED phenotype.

Neurodegenerative diseases

Interestingly, recent evidence implicates the E3 ligase activity of TRAF6 in the pathogenic aggregation of mutant proteins in neurodegenerative diseases such as Parkinson’s disease and Huntington disease. It was found that TRAF6 binds to misfolded mutant DJ-1, aSYN and N-HTT, proteins involved in the pathogenesis of the Parkinson’s disease and Huntington disease. Mutant DJ-1, aSYN and N-HTT proteins are all substrates of TRAF6. Instead of conventional K63-linked polyubiquitination, TRAF6 promotes atypical ubiquitination of DJ-1, aSYN and N-HTT with K6, K27, and K29 linkage formation, thereby stimulating aggregate formation of mutant DJ-1, aSYN and N-HTT in neurodegenerative diseases.

Chronic inflammation and infection

In light of their crucial importance in inflammatory and immune responses, it would be predicted that TRAF molecules may also contribute to chronic inflammation and infection. Although no genetic association of TRAFs and chronic inflammation or infection has been identified, recent evidence of alterations of TRAF protein levels supports this possibility. Notably, TRAF2 and TRAF3 are often degraded in response to signaling by the TNF-R superfamily. In contrast, TRAF1 expression is up-regulated by NF-κB activation in response to signaling by a variety of receptors, including TNF-R superfamily and cytokine receptors, etc.. The dynamic change of the stoichiometry of different TRAF molecules inside the cell impacts subsequent cellular responses to inflammatory or infectious stimuli. For example, the presence of TRAF1 stabilizes TRAF2, which plays a role in promoting proinflammtory responses in HeLa cells. More direct evidence was provided by a recent study demonstrating that TRAF1 is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans. This area warrants further investigation.

Conclusions

Since the first TRAFs were cloned in the mid 1990s, we have witnessed a remarkable progress in understanding the functions of TRAFs in signaling. TRAFs are now recognized as signal transducers of a wide variety of receptors, including the TNF-R superfamily, TLRs, NLRs, RLRs, IL-1R family, IL-17Rs, IFN receptors, TGFβ receptors, IL-2R, TCR, and C-type lectin receptors. Although initially defined as adaptor proteins, most TRAFs also function as E3 ubiquitin ligases through their RING finger domain. Furthermore, activation of TRAFs is exquisitely regulated by post-translational modifications, especially ubiquitination, which has become the subject of intense investigations during the past few years. Termination of TRAF activation could be achieved through either K48-linked polyubiquitination followed by proteosomal degradation or removal of K63-linked polyubiquitin chains catalyzed by deubiquitinases. Acting alone or in combination, TRAF-dependent signaling pathways regulate the activation of NF-κBs, MAPKs, or IRFs to control diverse cellular processes. Accumulating evidence obtained from TRAF-deficient mice demonstrates that each TRAF plays obligatory and distinct roles critical for innate immunity, adaptive immunity, embryonic development, and tissue homeostasis. The pivotal roles of TRAFs in host immunity are further highlighted by the finding that targeting TRAFs appears to be a common mechanism employed by pathogenic proteins of viruses and bacteria. Furthermore, the interest in TRAFs is also driven by recent discoveries that link TRAF genetic variations to human diseases such as cancers, autoimmune diseases, and immunodeficiencies. In conclusion, TRAFs are versatile and indispensable regulators of signal transduction and immune responses, and aberrant functions of TRAFs contribute to the pathogenesis of human diseases.

Perspectives

Despite the wealth of current knowledge about TRAFs, many key questions remain, which will drive the next stage of research in this important area. (1) What is the stoichiometric composition of TRAFs and other signaling proteins in each signaling complex? What are the dynamic kinetics of activation and spatial regulation of each TRAF molecule in response to each specific stimulus? Cutting-edge biochemical, proteomic, and imaging technologies will be needed to uncover these details. (2) How is the E3 ligase activity of each TRAF regulated precisely? What are the substrates of the E3 ligase activities of TRAF2, 3 and 5? Are there additional E3 ligases, deubiquitinases, kinases, and phosphatases that target different TRAFs? Are the enzymes targeting TRAFs regulated by TRAF-dependent signaling pathways? In vitro reconstitution experiments and ligase activity assays, high throughput screens for substrates and enzymes, and systems biology approaches will be needed to address these issues. (3) What are the molecular structures of each TRAF in complex with its specific signaling partner, substrate, or enzyme? This requires access to co-crystals containing TRAFs and their interacting partners, and the crystal structure of full-length TRAFs/substrates remains a challenge. (4) Are there additional pathogenic factors of invading microorganisms that target TRAFs during infections? If so, by what precise mechanisms? Yeast 2-hybrid screen, bioinformatic studies and proteomic approaches may be applied toward this end. (5) During pathogen infections, multiple TRAF-dependent signaling pathways are triggered either sequentially or simultaneously, including innate immune receptors (such as TLRs, NLRs and RLRs), adaptive immune receptors (such as TCR, CD40, OX-40 and 4-1BB), and cytokine receptors (such as IL-1R, IL-17R, IFN-Rs, and TβRs). How does each TRAF act in such complex and concerted signaling pathways in different cellular context during infection? Whether and how does each TRAF regulate the crosstalk between different immune signaling pathways? Responses of TRAF−/− mice, and especially cell type-specific TRAF−/− mice, to infections will be instrumental in addressing these questions. Sequential or simultaneous co-engagement of different immune receptors also needs to be investigated thoroughly in cultured cells. (6) What are the cell type-specific factors that dictate cell type-specific TRAF functions? For example, TRAF2 or TRAF3 deficiency leads to prolonged survival in B cells, but not in T cells or DCs. Genetic and systems biology approaches will be required for such studies. (7) Are there additional TRAF genetic alterations and SNPs associated with human diseases? Do epigenetic modifications of TRAFs contribute to disease conditions? How? Systematic and comprehensive analyses employing genetic, bioinformatic, and deep sequencing approaches will facilitate such investigation. Generation and examination of TRAF−/− or TRAF-transgenic mouse models of human diseases are also required to decipher the underlying mechanisms. Together, these future studies will undoubtedly yield valuable information to advance our understanding of TRAFs.

Given the importance of TRAFs in host immunity and in human diseases, the above future studies will also provide a platform for the development of therapeutic intervention of TRAF-mediated human diseases. For example, insights gained into the structures of each TRAF in complex with its specific signaling partner, substrate, or enzyme will guide the development of structure-based therapeutics. Small agonists and antagonists of TRAFs may be devised to enhance beneficial signaling pathways and to interfere with harmful ones, respectively. In this regard, cell-permeable TRAF6 decoy peptides potently inhibit TRAF6 signaling in cultured cells, and their therapeutic potential in disease settings are currently under investigation. A chemical compound 5-(4-methoxyarylimino)-2-N-(3,4-dichlorophenyl)-3-oxo-1,2,4-thiadiazolidine (P(3)-25), which possesses anti-bacterial and anti-fungal activities, specifically inhibits TRAF2-mediated NF-κB activation while enhancing TRAF2-mediated AP-1 activation. However, the diverse and cell type-specific functions of TRAFs may prevent systemic administration of therapeutic agents that directly target TRAFs, and local or cell-specific drug delivery needs to be exercised. Alternatively, therapeutic strategies may be designed to specifically manipulate TRAF-interacting partners or downstream signaling pathways. For example, pharmacological inhibitors for cIAP1/2 are currently at various stages of clinical trials for cancers, and may be applied to other TRAF-mediated diseases too. Further in-depth understanding of TRAF signaling pathways will serve as experimental framework to be translated into such therapeutic development.

Competing interests

The author declares that she has no competing financial interests.

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  94. 94.

    Kawai T Sato S Ishii KJ Coban C Hemmi H Yamamoto M Terai K Matsuda M Inoue J Uematsu S Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6Nat Immunol2004 510611068

    Not in our library10.1038/ni1118

  95. 95.

    Hacker H Redecke V Blagoev B Kratchmarova I Hsu LC Wang GG Kamps MP Raz E Wagner H Hacker G Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6Nature2006 439204207

    Not in our library10.1038/nature04369

  96. 96.

    Oganesyan G Saha SK Guo B He JQ Shahangian A Zarnegar B Perry A Cheng G Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral responseNature2006 439208211

    Not in our library10.1038/nature04374

  97. 97.

    Su X Li S Meng M Qian W Xie W Chen D Zhai Z Shu HB TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signalingEur J Immunol2006 36199206

    Not in our library10.1002/eji.200535415

  98. 98.

    Sasai M Tatematsu M Oshiumi H Funami K Matsumoto M Hatakeyama S Seya T Direct binding of TRAF2 and TRAF6 to TICAM-1/TRIF adaptor participates in activation of the Toll-like receptor 3/4 pathwayMol Immunol2010 4712831291

    Not in our library10.1016/j.molimm.2009.12.002

  99. 99.

    Takeshita F Ishii KJ Kobiyama K Kojima Y Coban C Sasaki S Ishii N Klinman DM Okuda K Akira S TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIFEur J Immunol2005 3524772485

    Not in our library10.1002/eji.200526151

  100. 100.

    Elinav E Strowig T Henao-Mejia J Flavell RA Regulation of the antimicrobial response by NLR proteinsImmunity2011 34665679

    Not in our library10.1016/j.immuni.2011.05.007

  101. 101.

    Bonardi V Cherkis K Nishimura MT Dangl JL A new eye on NLR proteins: focused on clarity or diffused by complexity?Curr Opin Immunol2012 244150

    Not in our library10.1016/j.coi.2011.12.006

  102. 102.

    Kersse K Bertrand MJ Lamkanfi M Vandenabeele P NOD-like receptors and the innate immune system: coping with danger, damage and deathCytokine Growth Factor Rev2011 22257276

    Not in our library10.1016/j.cytogfr.2011.09.003

  103. 103.

    Philpott DJ Girardin SE Nod-like receptors: sentinels at host membranesCurr Opin Immunol2010 22428434

    Not in our library10.1016/j.coi.2010.04.010

  104. 104.

    Maekawa T Kufer TA Schulze-Lefert P NLR functions in plant and animal immune systems: so far and yet so closeNat Immunol2011 12817826

    Not in our library10.1038/ni.2083

  105. 105.

    Labbe K McIntire CR Doiron K Leblanc PM Saleh M Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasomeImmunity2011 35897907

    Not in our library10.1016/j.immuni.2011.10.016

  106. 106.

    Brodsky IE Monack D NLR-mediated control of inflammasome assembly in the host response against bacterial pathogensSemin Immunol2009 21199207

    Not in our library10.1016/j.smim.2009.05.007

  107. 107.

    Tigno-Aranjuez JT Abbott DW Ubiquitination and phosphorylation in the regulation of NOD2 signaling and NOD2-mediated diseaseBiochim Biophys Acta1823 201220222028

    Not in our library10.1016/j.bbamcr.2012.03.017

  108. 108.

    Bertrand MJ Doiron K Labbe K Korneluk RG Barker PA Saleh M Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2Immunity2009 30789801

    Not in our library10.1016/j.immuni.2009.04.011

  109. 109.

    Marinis JM Homer CR McDonald C Abbott DW A novel motif in the Crohn’s disease susceptibility protein, NOD2, allows TRAF4 to down-regulate innate immune responsesJ Biol Chem2011 28619381950

    Not in our library10.1074/jbc.m110.189308

  110. 110.

    Damgaard RB Nachbur U Yabal M Wong WW Fiil BK Kastirr M Rieser E Rickard JA Bankovacki A Peschel C The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunityMol Cell2012 46746758

    Not in our library10.1016/j.molcel.2012.04.014

  111. 111.

    Abbott DW Yang Y Hutti JE Madhavarapu S Kelliher MA Cantley LC Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chainsMol Cell Biol2007 2760126025

    Not in our library10.1128/mcb.00270-07

  112. 112.

    Hasegawa M Fujimoto Y Lucas PC Nakano H Fukase K Nunez G Inohara N A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activationEMBO J2008 27373383

    Not in our library10.1038/sj.emboj.7601962

  113. 113.

    Marinis JM Hutti JE Homer CR Cobb BA Cantley LC McDonald C Abbott DW IkappaB kinase alpha phosphorylation of TRAF4 downregulates innate immune signalingMol Cell Biol2012 3224792489

    Not in our library10.1128/mcb.00106-12

  114. 114.

    Watanabe T Asano N Fichtner-Feigl S Gorelick PL Tsuji Y Matsumoto Y Chiba T Fuss IJ Kitani A Strober W NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathwayJ Clin Invest2010 12016451662

    Not in our library10.1172/jci39481

  115. 115.

    Sabbah A Chang TH Harnack R Frohlich V Tominaga K Dube PH Xiang Y Bose S Activation of innate immune antiviral responses by Nod2Nat Immunol2009 1010731080

    Not in our library10.1038/ni.1782

  116. 116.

    Loo YM Gale M Jr Immune signaling by RIG-I-like receptorsImmunity2011 34680692

    Not in our library10.1016/j.immuni.2011.05.003

  117. 117.

    Allen IC Wilson JE Schneider M Lich JD Roberts RA Arthur JC Woodford RM Davis BK Uronis JM Herfarth HH NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signalingImmunity2012 36742754

    Not in our library10.1016/j.immuni.2012.03.012

  118. 118.

    Allen IC Moore CB Schneider M Lei Y Davis BK Scull MA Gris D Roney KE Zimmermann AG Bowzard JB NLRX1 protein attenuates inflammatory responses to infection by interfering with the RIG-I-MAVS and TRAF6-NF-kappaB signaling pathwaysImmunity2011 34854865

    Not in our library10.1016/j.immuni.2011.03.026

  119. 119.

    Xia X Cui J Wang HY Zhu L Matsueda S Wang Q Yang X Hong J Songyang Z Chen ZJ NLRX1 negatively regulates TLR-induced NF-kappaB signaling by targeting TRAF6 and IKKImmunity2011 34843853

    Not in our library10.1016/j.immuni.2011.02.022

  120. 120.

    Schneider M Zimmermann AG Roberts RA Zhang L Swanson KV Wen H Davis BK Allen IC Holl EK Ye Z The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappaBNat Immunol2012 13823831

    Not in our library10.1038/ni.2378

  121. 121.

    Ramos HJ Gale M Jr RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunityCurr Opin Virol2011 1167176

    Not in our library10.1016/j.coviro.2011.04.004

  122. 122.

    Kato H Takahasi K Fujita T RIG-I-like receptors: cytoplasmic sensors for non-self RNAImmunol Rev2011 2439198

    Not in our library10.1111/j.1600-065x.2011.01052.x

  123. 123.

    Nakhaei P Genin P Civas A Hiscott J RIG-I-like receptors: sensing and responding to RNA virus infectionSemin Immunol2009 21215222

    Not in our library10.1016/j.smim.2009.05.001

  124. 124.

    Barral PM Sarkar D Su ZZ Barber GN DeSalle R Racaniello VR Fisher PB Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunityPharmacol Ther2009 124219234

    Not in our library10.1016/j.pharmthera.2009.06.012

  125. 125.

    Mikkelsen SS Jensen SB Chiliveru S Melchjorsen J Julkunen I Gaestel M Arthur JS Flavell RA Ghosh S Paludan SR RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1J Biol Chem2009 2841077410782

    Not in our library10.1074/jbc.m807272200

  126. 126.

    Saha SK Pietras EM He JQ Kang JR Liu SY Oganesyan G Shahangian A Zarnegar B Shiba TL Wang Y Regulation of antiviral responses by a direct and specific interaction between TRAF3 and CardifEMBO J2006 2532573263

    Not in our library10.1038/sj.emboj.7601220

  127. 127.

    Yoshida R Takaesu G Yoshida H Okamoto F Yoshioka T Choi Y Akira S Kawai T Yoshimura A Kobayashi T TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathwayJ Biol Chem2008 2833621136220

    Not in our library10.1074/jbc.m806576200

  128. 128.

    Maelfait J Beyaert R Emerging role of ubiquitination in antiviral RIG-I signalingMicrobiol Mol Biol Rev2012 763345

    Not in our library10.1128/mmbr.05012-11

  129. 129.

    Leung DW Basler CF Amarasinghe GK Molecular mechanisms of viral inhibitors of RIG-I-like receptorsTrends Microbiol2012 20139146

    Not in our library10.1016/j.tim.2011.12.005

  130. 130.

    Paz S Vilasco M Werden SJ Arguello M Joseph-Pillai D Zhao T Nguyen TL Sun Q Meurs EF Lin R A functional C-terminal TRAF3-binding site in MAVS participates in positive and negative regulation of the IFN antiviral responseCell Res2011 21895910

    Not in our library10.1038/cr.2011.2

  131. 131.

    Zhang P Reichardt A Liang H Aliyari R Cheng D Wang Y Xu F Cheng G Liu Y Single Amino Acid Substitutions Confer the Antiviral Activity of the TRAF3 Adaptor Protein onto TRAF5Sci Signal2012 5ra81

    Not in our library10.1126/scisignal.2003152

  132. 132.

    Wen C Yan Z Yang X Guan K Xu C Song T Zheng Z Wang W Wang Y Zhao M Identification of tyrosine-9 of MAVS as critical target for inducible phosphorylation that determines activationPLoS One2012 7e41687

    Not in our library10.1371/journal.pone.0041687

  133. 133.

    Huang Y Liu H Ge R Zhou Y Lou X Wang C UXT-V1 facilitates the formation of MAVS antiviral signalosome on mitochondriaJ Immunol2012 188358366

    Not in our library10.4049/jimmunol.1102079

  134. 134.

    Zhao T Yang L Sun Q Arguello M Ballard DW Hiscott J Lin R The NEMO adaptor bridges the nuclear factor-kappaB and interferon regulatory factor signaling pathwaysNat Immunol2007 8592600

    Not in our library10.1038/ni1465

  135. 135.

    Ryzhakov G Randow F SINTBAD, a novel component of innate antiviral immunity, shares a TBK1-binding domain with NAP1 and TANKEMBO J2007 2631803190

    Not in our library10.1038/sj.emboj.7601743

  136. 136.

    Zeng W Xu M Liu S Sun L Chen ZJ Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3Mol Cell2009 36315325

    Not in our library10.1016/j.molcel.2009.09.037

  137. 137.

    Parvatiyar K Barber GN Harhaj EW TAX1BP1 and A20 inhibit antiviral signaling by targeting TBK1-IKKi kinasesJ Biol Chem2010 2851499915009

    Not in our library10.1074/jbc.m110.109819

  138. 138.

    Belgnaoui SM Paz S Samuel S Goulet ML Sun Q Kikkert M Iwai K Dikic I Hiscott J Lin R Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS-TRAF3 complexCell Host Microbe2012 12211222

    Not in our library10.1016/j.chom.2012.06.009

  139. 139.
    TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. · 2010
    Not checked
  140. 140.

    Chattopadhyay S Marques JT Yamashita M Peters KL Smith K Desai A Williams BR Sen GC Viral apoptosis is induced by IRF-3-mediated activation of BaxEMBO J2010 2917621773

    Not in our library10.1038/emboj.2010.50

  141. 141.

    Konno H Yamamoto T Yamazaki K Gohda J Akiyama T Semba K Goto H Kato A Yujiri T Imai T TRAF6 establishes innate immune responses by activating NF-kappaB and IRF7 upon sensing cytosolic viral RNA and DNAPLoS One2009 4e5674

    Not in our library10.1371/journal.pone.0005674

  142. 142.

    Hu Y Wang J Yang B Zheng N Qin M Ji Y Lin G Tian L Wu X Wu L Guanylate binding protein 4 negatively regulates virus-induced type I IFN and antiviral response by targeting IFN regulatory factor 7J Immunol2011 18764566462

    Not in our library10.4049/jimmunol.1003691

  143. 143.

    Yoboua F Martel A Duval A Mukawera E Grandvaux N Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK betaJ Virol2010 8472677277

    Not in our library10.1128/jvi.00142-10

  144. 144.

    Mao AP Li S Zhong B Li Y Yan J Li Q Teng C Shu HB Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral responseJ Biol Chem2010 28594709476

    Not in our library10.1074/jbc.m109.071043

  145. 145.

    Choi YS Choi HJ Min JK Pyun BJ Maeng YS Park H Kim J Kim YM Kwon YG Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide productionBlood2009 11431173126

    Not in our library10.1182/blood-2009-02-203372

  146. 146.

    Funakoshi-Tago M Tago K Hayakawa M Tominaga S Ohshio T Sonoda Y Kasahara T TRAF6 is a critical signal transducer in IL-33 signaling pathwayCell Signal2008 2016791686

    Not in our library10.1016/j.cellsig.2008.05.013

  147. 147.

    Hu Y Shen F Crellin NK Ouyang W The IL-17 pathway as a major therapeutic target in autoimmune diseasesAnn N Y Acad Sci2011 12176076

    Not in our library10.1111/j.1749-6632.2010.05825.x

  148. 148.

    Reynolds JM Angkasekwinai P Dong C IL-17 family member cytokines: regulation and function in innate immunityCytokine Growth Factor Rev2010 21413423

    Not in our library10.1016/j.cytogfr.2010.10.002

  149. 149.

    Chang SH Dong C Signaling of interleukin-17 family cytokines in immunity and inflammationCell Signal2011 2310691075

    Not in our library10.1016/j.cellsig.2010.11.022

  150. 150.

    Shen F Gaffen SL Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapyCytokine2008 4192104

    Not in our library10.1016/j.cyto.2007.11.013

  151. 151.

    Gaffen SL Recent advances in the IL-17 cytokine familyCurr Opin Immunol2011 23613619

    Not in our library10.1016/j.coi.2011.07.006

  152. 152.

    Gaffen SL Structure and signalling in the IL-17 receptor familyNat Rev Immunol2009 9556567

    Not in our library10.1038/nri2586

  153. 153.

    Sun D Novotny M Bulek K Liu C Li X Hamilton T Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF)Nat Immunol2011 12853860

    Not in our library10.1038/ni.2081

  154. 154.

    Qian Y Liu C Hartupee J Altuntas CZ Gulen MF Jane-Wit D Xiao J Lu Y Giltiay N Liu J The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory diseaseNat Immunol2007 8247256

    Not in our library10.1038/ni1439

  155. 155.

    Chang SH Park H Dong C Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptorJ Biol Chem2006 2813560335607

    Not in our library10.1074/jbc.c600256200

  156. 156.

    Rong Z Cheng L Ren Y Li Z Li Y Li X Li H Fu XY Chang Z Interleukin-17F signaling requires ubiquitination of interleukin-17 receptor via TRAF6Cell Signal2007 1915141520

    Not in our library10.1016/j.cellsig.2007.01.025

  157. 157.

    Sonder SU Saret S Tang W Sturdevant DE Porcella SF Siebenlist U IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanismsJ Biol Chem2011 2861288112890

    Not in our library10.1074/jbc.m110.199547

  158. 158.

    Schwandner R Yamaguchi K Cao Z Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transductionJ Exp Med2000 19112331240

    Not in our library10.1084/jem.191.7.1233

  159. 159.

    Chang SH Dong C IL-17F: regulation, signaling and function in inflammationCytokine2009 46711

    Not in our library10.1016/j.cyto.2008.12.024

  160. 160.

    Shen F Li N Gade P Kalvakolanu DV Weibley T Doble B Woodgett JR Wood TD Gaffen SL IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domainSci Signal2009 2ra8

    Not in our library10.1126/scisignal.2000066

  161. 161.

    Bulek K Liu C Swaidani S Wang L Page RC Gulen MF Herjan T Abbadi A Qian W Sun D The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammationNat Immunol2011 12844852

    Not in our library10.1038/ni.2080

  162. 162.

    Qu F Gao H Zhu S Shi P Zhang Y Liu Y Jallal B Yao Y Shi Y Qian Y TRAF6-dependent Act1 phosphorylation by the IkappaB kinase-related kinases suppresses interleukin-17-induced NF-kappaB activationMol Cell Biol2012 3239253937

    Not in our library10.1128/mcb.00268-12

  163. 163.

    Zhu S Pan W Shi P Gao H Zhao F Song X Liu Y Zhao L Li X Shi Y Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signalingJ Exp Med2010 20726472662

    Not in our library10.1084/jem.20100703

  164. 164.

    Zepp JA Liu C Qian W Wu L Gulen MF Kang Z Li X Cutting edge: TNF receptor-associated factor 4 restricts IL-17-mediated pathology and signaling processesJ Immunol2012 1893337

    Not in our library10.4049/jimmunol.1200470

  165. 165.

    Yang CH Murti A Pfeffer LM Interferon induces NF-kappa B-inducing kinase/tumor necrosis factor receptor-associated factor-dependent NF-kappa B activation to promote cell survivalJ Biol Chem2005 2803153031536

    Not in our library10.1074/jbc.m503120200

  166. 166.

    Xie YF Cui YB Hui XW Wang L Ma XL Chen H Wang X Huang BR Interaction of IFNlambdaR1 with TRAF6 regulates NF-kappaB activation and IFNlambdaR1 stabilityJ Cell Biochem2012 11333713379

    Not in our library10.1002/jcb.24213

  167. 167.

    Sorrentino A Thakur N Grimsby S Marcusson A von Bulow V Schuster N Zhang S Heldin CH Landstrom M The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent mannerNat Cell Biol2008 1011991207

    Not in our library10.1038/ncb1780

  168. 168.

    Yamashita M Fatyol K Jin C Wang X Liu Z Zhang YE TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-betaMol Cell2008 31918924

    Not in our library10.1016/j.molcel.2008.09.002

  169. 169.

    Mu Y Sundar R Thakur N Ekman M Gudey SK Yakymovych M Hermansson A Dimitriou H Bengoechea-Alonso MT Ericsson J TRAF6 ubiquitinates TGFbeta type I receptor to promote its cleavage and nuclear translocation in cancerNat Commun2011 2330

    Not in our library10.1038/ncomms1332

  170. 170.
    TRAF6 mediates IL-1β/LPS-induced suppression of TGF-β signaling through its interaction with the type III TGF-β receptor. · 2012
    Not checked
  171. 171.

    Wang C McPherson AJ Jones RB Kawamura KS Lin GH Lang PA Ambagala T Pellegrini M Calzascia T Aidarus N Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infectionJ Exp Med2012 2097791

    Not in our library10.1084/jem.20110675

  172. 172.

    Motegi H Shimo Y Akiyama T Inoue J TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signalingGenes Cells2011 16179189

    Not in our library10.1111/j.1365-2443.2010.01474.x

  173. 173.

    Tsitsikov EN Laouini D Dunn IF Sannikova TY Davidson L Alt FW Geha RS TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient miceImmunity2001 15647657

    Not in our library10.1016/s1074-7613(01)00207-2

  174. 174.

    Sun L Deng L Ea CK Xia ZP Chen ZJ The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytesMol Cell2004 14289301

    Not in our library10.1016/s1097-2765(04)00236-9

  175. 175.

    Bidere N Snow AL Sakai K Zheng L Lenardo MJ Caspase-8 regulation by direct interaction with TRAF6 in T cell receptor-induced NF-kappaB activationCurr Biol2006 1616661671

    Not in our library10.1016/j.cub.2006.06.062

  176. 176.

    Xie JJ Liang JQ Diao LH Altman A Li Y TNFR-Associated Factor 6 Regulates TCR Signaling via Interaction with and Modification of LAT AdapterJ Immunol2013 19040274036

    Not in our library10.4049/jimmunol.1202742

  177. 177.

    Gorjestani S Darnay BG Lin X TRAF6 and TAK1 play essential roles in C-type lectin receptor signaling in response to Candida albicans infectionJ Biol Chem2012 2874414344150

    Not in our library10.1074/jbc.m112.414276

  178. 178.

    Hinz M Stilmann M Arslan SC Khanna KK Dittmar G Scheidereit C A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activationMol Cell2010 406374

    Not in our library10.1016/j.molcel.2010.09.008

  179. 179.

    Habelhah H Emerging complexity of protein ubiquitination in the NF-kappaB pathwayGenes Cancer2010 1735747

    Not in our library10.1177/1947601910382900

  180. 180.

    Alvarez SE Harikumar KB Hait NC Allegood J Strub GM Kim EY Maceyka M Jiang H Luo C Kordula T Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2Nature2010 46510841088

    Not in our library10.1038/nature09128

  181. 181.

    Yin Q Lamothe B Darnay BG Wu H Structural basis for the lack of E2 interaction in the RING domain of TRAF2Biochemistry2009 481055810567

    Not in our library10.1021/bi901462e

  182. 182.

    Zhang L Blackwell K Shi Z Habelhah H The RING domain of TRAF2 plays an essential role in the inhibition of TNFalpha-induced cell death but not in the activation of NF-kappaBJ Mol Biol2010 396528539

    Not in our library10.1016/j.jmb.2010.01.008

  183. 183.

    Silke J The regulation of TNF signalling: what a tangled web we weaveCurr Opin Immunol2011 23620626

    Not in our library10.1016/j.coi.2011.08.002

  184. 184.

    Habelhah H Takahashi S Cho SG Kadoya T Watanabe T Ronai Z Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-kappaBEMBO J2004 23322332

    Not in our library10.1038/sj.emboj.7600044

  185. 185.

    Kayagaki N Phung Q Chan S Chaudhari R Quan C O’Rourke KM Eby M Pietras E Cheng G Bazan JF DUBA: a deubiquitinase that regulates type I interferon productionScience2007 31816281632

    Not in our library10.1126/science.1145918

  186. 186.

    Lamothe B Campos AD Webster WK Gopinathan A Hur L Darnay BG The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKLJ Biol Chem2008 2832487124880

    Not in our library10.1074/jbc.m802749200

  187. 187.

    Fan Y Yu Y Shi Y Sun W Xie M Ge N Mao R Chang A Xu G Schneider MD Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activationJ Biol Chem2010 28553475360

    Not in our library10.1074/jbc.m109.076976

  188. 188.

    Conze DB Wu CJ Thomas JA Landstrom A Ashwell JD Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activationMol Cell Biol2008 2835383547

    Not in our library10.1128/mcb.02098-07

  189. 189.

    Saitoh T Satoh T Yamamoto N Uematsu S Takeuchi O Kawai T Akira S Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cellsImmunity2011 34352363

    Not in our library10.1016/j.immuni.2011.03.010

  190. 190.

    Yang WL Wang J Chan CH Lee SW Campos AD Lamothe B Hur L Grabiner BC Lin X Darnay BG The E3 ligase TRAF6 regulates Akt ubiquitination and activationScience2009 32511341138

    Not in our library10.1126/science.1175065

  191. 191.

    Liu A Gong P Hyun SW Wang KZ Cates EA Perkins D Bannerman DD Puche AC Toshchakov VY Fang S TRAF6 protein couples Toll-like receptor 4 signaling to Src family kinase activation and opening of paracellular pathway in human lung microvascular endotheliaJ Biol Chem2012 2871613216145

    Not in our library10.1074/jbc.m111.310102

  192. 192.

    Sebban-Benin H Pescatore A Fusco F Pascuale V Gautheron J Yamaoka S Moncla A Ursini MV Courtois G Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis of a new NEMO mutation causing incontinentia pigmentiHum Mol Genet2007 1628052815

    Not in our library10.1093/hmg/ddm237

  193. 193.

    Napolitano G Mirra S Monfregola J Lavorgna A Leonardi A Ursini MV NESCA: a new NEMO/IKKgamma and TRAF6 interacting proteinJ Cell Physiol2009 220410417

    Not in our library10.1002/jcp.21782

  194. 194.

    Carpentier I Coornaert B Beyaert R Smurf2 is a TRAF2 binding protein that triggers TNF-R2 ubiquitination and TNF-R2-induced JNK activationBiochem Biophys Res Commun2008 374752757

    Not in our library10.1016/j.bbrc.2008.07.103

  195. 195.

    Ning S Campos AD Darnay BG Bentz GL Pagano JS TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1Mol Cell Biol2008 2865366546

    Not in our library10.1128/mcb.00785-08

  196. 196.

    Chang Foreman HC Van Scoy S Cheng TF Reich NC Activation of interferon regulatory factor 5 by site specific phosphorylationPLoS One2012 7e33098

    Not in our library10.1371/journal.pone.0033098

  197. 197.

    Balkhi MY Fitzgerald KA Pitha PM Functional regulation of MyD88-activated interferon regulatory factor 5 by K63-linked polyubiquitinationMol Cell Biol2008 2872967308

    Not in our library10.1128/mcb.00662-08

  198. 198.

    Schichl YM Resch U Lemberger CE Stichlberger D de Martin R Novel phosphorylation-dependent ubiquitination of tristetraprolin by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) and tumor necrosis factor receptor-associated factor 2 (TRAF2)J Biol Chem2011 2863846638477

    Not in our library10.1074/jbc.m111.254888

  199. 199.

    Shi CS Kehrl JH TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control TLR4-induced autophagySci Signal2010 3ra42

    Not in our library10.1126/scisignal.2000751

  200. 200.

    Inomata M Niida S Shibata K Into T Regulation of Toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20Cell Mol Life Sci2012 69963979

    Not in our library10.1007/s00018-011-0819-y

  201. 201.

    Liu C Qian W Qian Y Giltiay NV Lu Y Swaidani S Misra S Deng L Chen ZJ Li X Act1, a U-box E3 ubiquitin ligase for IL-17 signalingSci Signal2009 2ra63

    Not in our library10.1126/scisignal.2000382

  202. 202.

    Siednienko J Jackson R Mellett M Delagic N Yang S Wang B Tang LS Callanan JJ Mahon BP Moynagh PN Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferonsNat Immunol2012 1310551062

    Not in our library10.1038/ni.2429

  203. 203.
    The E3 Ubiquitin Ligase Triad3A Negatively Regulates the RIG-I/MAVS Signaling Pathway by Targeting TRAF3 for Degradation · 2009
    No notice
  204. 204.

    Zhong B Liu X Wang X Chang SH Wang A Reynolds JM Dong C Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25Nat Immunol2012 1311101117

    Not in our library10.1038/ni.2427

  205. 205.

    Li X Yang Y Ashwell JD TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2Nature2002 416345347

    Not in our library10.1038/416345a

  206. 206.

    Wu CJ Conze DB Li X Ying SX Hanover JA Ashwell JD TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitinationEMBO J2005 2418861898

    Not in our library10.1038/sj.emboj.7600649

  207. 207.

    Dupoux A Cartier J Cathelin S Filomenko R Solary E Dubrez-Daloz L cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligandBlood2009 113175185

    Not in our library10.1182/blood-2008-02-137919

  208. 208.

    Chang EJ Ha J Kang SS Lee ZH Kim HH AWP1 binds to tumor necrosis factor receptor-associated factor 2 (TRAF2) and is involved in TRAF2-mediated nuclear factor-kappaB signalingInt J Biochem Cell Biol2011 4316121620

    Not in our library10.1016/j.biocel.2011.07.010

  209. 209.
    SOCS2-induced proteasome-dependent TRAF6 degradation: a common anti-inflammatory pathway for control of innate immune responses. · 2012
    Not checked
  210. 210.

    Gudi R Barkinge J Hawkins S Prabhakar B Kanteti P Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaBJ Environ Pathol Toxicol Oncol2009 282538

    Not in our library10.1615/jenvironpatholtoxicoloncol.v28.i1.30

  211. 211.

    Zhou L Ma Q Shi H Huo K NUMBL interacts with TRAF6 and promotes the degradation of TRAF6Biochem Biophys Res Commun2010 392409414

    Not in our library10.1016/j.bbrc.2010.01.037

  212. 212.

    Tao T Cheng C Ji Y Xu G Zhang J Zhang L Shen A Numbl inhibits glioma cell migration and invasion by suppressing TRAF5-mediated NF-kappaB activationMol Biol Cell2012 2326352644

    Not in our library10.1091/mbc.e11-09-0805

  213. 213.

    Jang KW Lee KH Kim SH Jin T Choi EY Jeon HJ Kim E Han YS Chung JH Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-kappaB inactivation to regulate breast cancer cell invasionJ Cell Biochem2011 11236123620

    Not in our library10.1002/jcb.23292

  214. 214.

    Wang J Hu Y Deng WW Sun B Negative regulation of Toll-like receptor signaling pathwayMicrobes Infect2009 11321327

    Not in our library10.1016/j.micinf.2008.12.011

  215. 215.

    Chapard C Hohl D Huber M The role of the TRAF-interacting protein in proliferation and differentiationExp Dermatol2012 21321326

    Not in our library10.1111/j.1600-0625.2012.01477.x

  216. 216.

    Gonzalez-Navajas JM Law J Nguyen KP Bhargava M Corr MP Varki N Eckmann L Hoffman HM Lee J Raz E Interleukin 1 receptor signaling regulates DUBA expression and facilitates Toll-like receptor 9-driven antiinflammatory cytokine productionJ Exp Med2010 20727992807

    Not in our library10.1084/jem.20101326

  217. 217.

    Shembade N Ma A Harhaj EW Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexesScience2010 32711351139

    Not in our library10.1126/science.1182364

  218. 218.

    Li L Soetandyo N Wang Q Ye Y The zinc finger protein A20 targets TRAF2 to the lysosomes for degradationBiochim Biophys Acta2009 1793346353

    Not in our library10.1016/j.bbamcr.2008.09.013

  219. 219.

    Liang J Saad Y Lei T Wang J Qi D Yang Q Kolattukudy PE Fu M MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappaB signalingJ Exp Med2010 20729592973

    Not in our library10.1084/jem.20092641

  220. 220.

    Lee EG Boone DL Chai S Libby SL Chien M Lodolce JP Ma A Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient miceScience2000 28923502354

    Not in our library10.1126/science.289.5488.2350

  221. 221.

    Zhang J Stirling B Temmerman ST Ma CA Fuss IJ Derry JM Jain A Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient miceJ Clin Invest2006 11630423049

    Not in our library10.1172/jci28746

  222. 222.

    Trompouki E Hatzivassiliou E Tsichritzis T Farmer H Ashworth A Mosialos G CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family membersNature2003 424793796

    Not in our library10.1038/nature01803

  223. 223.

    Jin W Chang M Paul EM Babu G Lee AJ Reiley W Wright A Zhang M You J Sun SC Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in miceJ Clin Invest2008 11818581866

    Not in our library10.1172/jci34257

  224. 224.

    Kovalenko A Chable-Bessia C Cantarella G Israel A Wallach D Courtois G The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitinationNature2003 424801805

    Not in our library10.1038/nature01802

  225. 225.

    Mahul-Mellier AL Pazarentzos E Datler C Iwasawa R AbuAli G Lin B Grimm S De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNFCell Death Differ2012 19891899

    Not in our library10.1038/cdd.2011.185

  226. 226.

    He X Li Y Li C Liu LJ Zhang XD Liu Y Shu HB USP2a negatively regulates IL-1beta- and virus-induced NF-kappaB activation by deubiquitinating TRAF6J Mol Cell Biol2013 53947

    Not in our library10.1093/jmcb/mjs024

  227. 227.

    Xiao N Li H Luo J Wang R Chen H Chen J Wang P Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha-induced cancer cell migrationBiochem J2012 441979986

    Not in our library10.1042/bj20111358

  228. 228.

    Zhou F Zhang X van Dam H Ten Dijke P Huang H Zhang L Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activationJ Biol Chem2012 2871100211010

    Not in our library10.1074/jbc.m111.328187

  229. 229.

    Yasunaga J Lin FC Lu X Jeang KT Ubiquitin-specific peptidase 20 targets TRAF6 and human T cell leukemia virus type 1 tax to negatively regulate NF-kappaB signalingJ Virol2011 8562126219

    Not in our library10.1128/jvi.00079-11

  230. 230.

    Li S Zheng H Mao AP Zhong B Li Y Liu Y Gao Y Ran Y Tien P Shu HB Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6J Biol Chem2010 28542914297

    Not in our library10.1074/jbc.m109.074971

  231. 231.

    Boone DL Turer EE Lee EG Ahmad RC Wheeler MT Tsui C Hurley P Chien M Chai S Hitotsumatsu O The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responsesNat Immunol2004 510521060

    Not in our library10.1038/ni1110

  232. 232.

    Srivastav S Kar S Chande AG Mukhopadhyaya R Das PK Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signaling, to subvert host immune responseJ Immunol2012 189924934

    Not in our library10.4049/jimmunol.1102845

  233. 233.

    Kato T Jr Gotoh Y Hoffmann A Ono Y Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1Genes Cells2008 13509520

    Not in our library10.1111/j.1365-2443.2008.01182.x

  234. 234.

    Oussa NA Soumounou Y Sabbagh L TRAF1 phosphorylation on Serine 139 modulates NF-kappaB activity downstream of 4-1BB in T cellsBiochem Biophys Res Commun2013 432129134

    Not in our library10.1016/j.bbrc.2013.01.073

  235. 235.

    Thomas GS Zhang L Blackwell K Habelhah H Phosphorylation of TRAF2 within its RING domain inhibits stress-induced cell death by promoting IKK and suppressing JNK activationCancer Res2009 6936653672

    Not in our library10.1158/0008-5472.can-08-4867

  236. 236.

    Li S Wang L Dorf ME PKC phosphorylation of TRAF2 mediates IKKalpha/beta recruitment and K63-linked polyubiquitinationMol Cell2009 333042

    Not in our library10.1016/j.molcel.2008.11.023

  237. 237.

    Zhang L Blackwell K Altaeva A Shi Z Habelhah H TRAF2 phosphorylation promotes NF-kappaB-dependent gene expression and inhibits oxidative stress-induced cell deathMol Biol Cell2011 22128140

    Not in our library10.1091/mbc.e10-06-0556

  238. 238.

    Shen RR Zhou AY Kim E Lim E Habelhah H Hahn WC IkappaB Kinase varepsilon Phosphorylates TRAF2 To Promote Mammary Epithelial Cell TransformationMol Cell Biol2012 3247564768

    Not in our library10.1128/mcb.00468-12

  239. 239.

    Chantzoura E Prinarakis E Panagopoulos D Mosialos G Spyrou G Glutaredoxin-1 regulates TRAF6 activation and the IL-1 receptor/TLR4 signallingBiochem Biophys Res Commun2010 403335339

    Not in our library10.1016/j.bbrc.2010.11.029

  240. 240.

    Jiang J Tang H Mechanism of inhibiting type I interferon induction by hepatitis B virus X proteinProtein Cell2010 111061117

    Not in our library10.1007/s13238-010-0141-8

  241. 241.

    Sweet CR Conlon J Golenbock DT Goguen J Silverman N YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transductionCell Microbiol2007 927002715

    Not in our library10.1111/j.1462-5822.2007.00990.x

  242. 242.

    Alff PJ Sen N Gorbunova E Gavrilovskaya IN Mackow ER The NY-1 hantavirus Gn cytoplasmic tail coprecipitates TRAF3 and inhibits cellular interferon responses by disrupting TBK1-TRAF3 complex formationJ Virol2008 8291159122

    Not in our library10.1128/jvi.00290-08

  243. 243.
    Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex · 2009
    No notice
  244. 244.

    Harte MT Haga IR Maloney G Gray P Reading PC Bartlett NW Smith GL Bowie A O’Neill LA The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defenseJ Exp Med2003 197343351

    Not in our library10.1084/jem.20021652

  245. 245.

    Devergne O Hatzivassiliou E Izumi KM Kaye KM Kleijnen MF Kieff E Mosialos G Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activationMol Cell Biol1996 1670987108

    Not in our library10.1128/mcb.16.12.7098

  246. 246.

    Brown KD Hostager BS Bishop GA Differential signaling and tumor necrosis factor receptor-associated factor (TRAF) degradation mediated by CD40 and the Epstein-Barr virus oncoprotein latent membrane protein 1 (LMP1)J Exp Med2001 193943954

    Not in our library10.1084/jem.193.8.943

  247. 247.

    Xie P Hostager BS Bishop GA Requirement for TRAF3 in Signaling by LMP1 But Not CD40 in B LymphocytesJ Exp Med2004 199661671

    Not in our library10.1084/jem.20031255

  248. 248.

    Kraus ZJ Nakano H Bishop GA TRAF5 is a critical mediator of in vitro signals and in vivo functions of LMP1, the viral oncogenic mimic of CD40Proc Natl Acad Sci USA2009 1061714017145

    Not in our library10.1073/pnas.0903786106

  249. 249.

    Arcipowski KM Stunz LL Graham JP Kraus ZJ Vanden Bush TJ Bishop GA Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1)J Biol Chem2011 28699489955

    Not in our library10.1074/jbc.m110.185983

  250. 250.

    Thurau M Everett H Tapernoux M Tschopp J Thome M The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosisCell Death Differ2006 1315771585

    Not in our library10.1038/sj.cdd.4401847

  251. 251.

    Mishra R Chhatbar C Singh SK HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microgliaJ Neuroinflammation2012 9131

    Not in our library10.1186/1742-2094-9-131

  252. 252.

    Hou J Wang P Lin L Liu X Ma F An H Wang Z Cao X MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2J Immunol2009 18321502158

    Not in our library10.4049/jimmunol.0900707

  253. 253.

    Paik JH Jang JY Jeon YK Kim WY Kim TM Heo DS Kim CW MicroRNA-146a downregulates NFkappaB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphomaClin Cancer Res2011 1747614771

    Not in our library10.1158/1078-0432.ccr-11-0494

  254. 254.

    Hagemeier SR Barlow EA Kleman AA Kenney SC The Epstein-Barr virus BRRF1 protein, Na, induces lytic infection in a TRAF2- and p53-dependent mannerJ Virol2011 8543184329

    Not in our library10.1128/jvi.01856-10

  255. 255.

    Guasparri I Wu H Cesarman E The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signallingEMBO Rep2006 7114119

    Not in our library10.1038/sj.embor.7400580

  256. 256.

    Liu X Fitzgerald K Kurt-Jones E Finberg R Knipe DM Herpesvirus tegument protein activates NF-kappaB signaling through the TRAF6 adaptor proteinProc Natl Acad Sci USA2008 1051133511339

    Not in our library10.1073/pnas.0801617105

  257. 257.

    Oyoshi MK Bryce P Goya S Pichavant M Umetsu DT Oettgen HC Tsitsikov EN TNF receptor-associated factor 1 expressed in resident lung cells is required for the development of allergic lung inflammationJ Immunol2008 18018781885

    Not in our library10.4049/jimmunol.180.3.1878

  258. 258.

    Regnier CH Masson R Kedinger V Textoris J Stoll I Chenard MP Dierich A Tomasetto C Rio MC Impaired neural tube closure, axial skeleton malformations, and tracheal ring disruption in TRAF4-deficient miceProc Natl Acad Sci USA2002 9955855590

    Not in our library10.1073/pnas.052124799

  259. 259.

    Shiels H Li X Schumacker PT Maltepe E Padrid PA Sperling A Thompson CB Lindsten T TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungsAm J Pathol2000 157679688

    Not in our library10.1016/s0002-9440(10)64578-6

  260. 260.

    Blaise S Kneib M Rousseau A Gambino F Chenard MP Messadeq N Muckenstrum M Alpy F Tomasetto C Humeau Y In vivo evidence that TRAF4 is required for central nervous system myelin homeostasisPLoS One2012 7e30917

    Not in our library10.1371/journal.pone.0030917

  261. 261.

    Piao JH Hasegawa M Heissig B Hattori K Takeda K Iwakura Y Okumura K Inohara N Nakano H Tumor necrosis factor receptor-associated factor (TRAF) 2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel diseaseJ Biol Chem2011 2861787917888

    Not in our library10.1074/jbc.m111.221853

  262. 262.

    Piao JH Yagita H Okumura K Nakano H Aberrant accumulation of interleukin-10-secreting neutrophils in TRAF2-deficient miceImmunol Cell Biol2012 90881888

    Not in our library10.1038/icb.2012.22

  263. 263.

    He JQ Zarnegar B Oganesyan G Saha SK Yamazaki S Doyle SE Dempsey PW Cheng G Rescue of TRAF3-null mice by p100 NF-kappa B deficiencyJ Exp Med2006 20324132418

    Not in our library10.1084/jem.20061166

  264. 264.

    Lomaga MA Yeh WC Sarosi I Duncan GS Furlonger C Ho A Morony S Capparelli C Van G Kaufman S TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signalingGenes Dev1999 1310151024

    Not in our library10.1101/gad.13.8.1015

  265. 265.

    Naito A Azuma S Tanaka S Miyazaki T Takaki S Takatsu K Nakao K Nakamura K Katsuki M Yamamoto T Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient miceGenes Cells1999 4353362

    Not in our library10.1046/j.1365-2443.1999.00265.x

  266. 266.

    Bryce PJ Oyoshi MK Kawamoto S Oettgen HC Tsitsikov EN TRAF1 regulates Th2 differentiation, allergic inflammation and nuclear localization of the Th2 transcription factor, NIP45Int Immunol2006 18101111

    Not in our library10.1093/intimm/dxh354

  267. 267.

    Yeh WC Shahinian A Speiser D Kraunus J Billia F Wakeham A de la Pompa JL Ferrick D Hum B Iscove N Early lethality, functional NF-kappaB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient miceImmunity1997 7715725

    Not in our library10.1016/s1074-7613(00)80391-x

  268. 268.

    Chen Z Sheng L Shen H Zhao Y Wang S Brink R Rui L Hepatic TRAF2 regulates glucose metabolism through enhancing glucagon responsesDiabetes2012 61566573

    Not in our library10.2337/db11-0474

  269. 269.

    Xu Y Cheng G Baltimore D Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responsesImmunity1996 5407415

    Not in our library10.1016/s1074-7613(00)80497-5

  270. 270.

    Xie P Stunz LL Larison KD Yang B Bishop GA Tumor necrosis factor receptor-associated factor 3 is a critical regulator of B cell homeostasis in secondary lymphoid organsImmunity2007 27253267

    Not in our library10.1016/j.immuni.2007.07.012

  271. 271.

    Moore CR Liu Y Shao CS Covey LR Morse HC 3rd Xie P Specific deletion of TRAF3 in B lymphocytes leads to B lymphoma development in miceLeukemia2012 2611221127

    Not in our library10.1038/leu.2011.309

  272. 272.

    Xie P Poovassery J Stunz LL Smith SM Schultz ML Carlin LE Bishop GA Enhanced Toll-like receptor (TLR) responses of TNFR-associated factor 3 (TRAF3)-deficient B lymphocytesJ Leukoc Biol2011 9011491157

    Not in our library10.1189/jlb.0111044

  273. 273.

    Cherfils-Vicini J Vingert B Varin A Tartour E Fridman WH Sautes-Fridman C Regnier CH Cremer I Characterization of immune functions in TRAF4-deficient miceImmunology2008 124562574

    Not in our library10.1111/j.1365-2567.2008.02810.x

  274. 274.

    Nakano H Sakon S Koseki H Takemori T Tada K Matsumoto M Munechika E Sakai T Shirasawa T Akiba H Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activationProc Natl Acad Sci USA1999 9698039808

    Not in our library10.1073/pnas.96.17.9803

  275. 275.

    So T Salek-Ardakani S Nakano H Ware CF Croft M TNF receptor-associated factor 5 limits the induction of Th2 immune responsesJ Immunol2004 17242924297

    Not in our library10.4049/jimmunol.172.7.4292

  276. 276.

    Shimo Y Yanai H Ohshima D Qin J Motegi H Maruyama Y Hori S Inoue J Akiyama T TRAF6 directs commitment to regulatory T cells in thymocytesGenes Cells2011 16437447

    Not in our library10.1111/j.1365-2443.2011.01500.x

  277. 277.

    Kobayashi T Walsh PT Walsh MC Speirs KM Chiffoleau E King CG Hancock WW Caamano JH Hunter CA Scott P TRAF6 is a critical factor for dendritic cell maturation and developmentImmunity2003 19353363

    Not in our library10.1016/s1074-7613(03)00230-9

  278. 278.

    Yang YJ Chen W Carrigan SO Chen WM Roth K Akiyama T Inoue J Marshall JS Berman JN Lin TJ TRAF6 specifically contributes to FcepsilonRI-mediated cytokine production but not mast cell degranulationJ Biol Chem2008 2833211032118

    Not in our library10.1074/jbc.m802610200

  279. 279.

    Naito A Yoshida H Nishioka E Satoh M Azuma S Yamamoto T Nishikawa S Inoue J TRAF6-deficient mice display hypohidrotic ectodermal dysplasiaProc Natl Acad Sci USA2002 9987668771

    Not in our library10.1073/pnas.132636999

  280. 280.

    Kobayashi T Kim TS Jacob A Walsh MC Kadono Y Fuentes-Panana E Yoshioka T Yoshimura A Yamamoto M Kaisho T TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responsesPLoS One2009 4e4736

    Not in our library10.1371/journal.pone.0004736

  281. 281.

    King CG Kobayashi T Cejas PJ Kim T Yoon K Kim GK Chiffoleau E Hickman SP Walsh PT Turka LA TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasisNat Med2006 1210881092

    Not in our library10.1038/nm1449

  282. 282.

    King CG Buckler JL Kobayashi T Hannah JR Bassett G Kim T Pearce EL Kim GG Turka LA Choi Y Cutting edge: requirement for TRAF6 in the induction of T cell anergyJ Immunol2008 1803438

    Not in our library10.4049/jimmunol.180.1.34

  283. 283.

    Pearce EL Walsh MC Cejas PJ Harms GM Shen H Wang LS Jones RG Choi Y Enhancing CD8 T-cell memory by modulating fatty acid metabolismNature2009 460103107

    Not in our library10.1038/nature08097

  284. 284.

    Cejas PJ Walsh MC Pearce EL Han D Harms GM Artis D Turka LA Choi Y TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2Blood2010 11547504757

    Not in our library10.1182/blood-2009-09-242768

  285. 285.

    Paul PK Kumar A TRAF6 coordinates the activation of autophagy and ubiquitin-proteasome systems in atrophying skeletal muscleAutophagy2011 7555556

    Not in our library10.4161/auto.7.5.15102

  286. 286.

    Paul PK Gupta SK Bhatnagar S Panguluri SK Darnay BG Choi Y Kumar A Targeted ablation of TRAF6 inhibits skeletal muscle wasting in miceJ Cell Biol2010 19113951411

    Not in our library10.1083/jcb.201006098

  287. 287.

    Hindi SM Paul PK Dahiya S Mishra V Bhatnagar S Kuang S Choi Y Kumar A Reciprocal Interaction between TRAF6 and Notch Signaling Regulates Adult Myofiber Regeneration upon InjuryMol Cell Biol2012 3248334845

    Not in our library10.1128/mcb.00717-12

  288. 288.

    Paul PK Bhatnagar S Mishra V Srivastava S Darnay BG Choi Y Kumar A The E3 ubiquitin ligase TRAF6 intercedes in starvation-induced skeletal muscle atrophy through multiple mechanismsMol Cell Biol2012 3212481259

    Not in our library10.1128/mcb.06351-11

  289. 289.

    Lin WJ Su YW Lu YC Hao Z Chio II Chen NJ Brustle A Li WY Mak TW Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 signaling that contributes to autoimmunityProc Natl Acad Sci USA2012 1081835418359

    Not in our library10.1073/pnas.1109427108

  290. 290.

    Arron JR Pewzner-Jung Y Walsh MC Kobayashi T Choi Y Regulation of the subcellular localization of tumor necrosis factor receptor-associated factor (TRAF)2 by TRAF1 reveals mechanisms of TRAF2 signalingJ Exp Med2002 196923934

    Not in our library10.1084/jem.20020774

  291. 291.

    Missiou A Kostlin N Varo N Rudolf P Aichele P Ernst S Munkel C Walter C Stachon P Sommer B Tumor necrosis factor receptor-associated factor 1 (TRAF1) deficiency attenuates atherosclerosis in mice by impairing monocyte recruitment to the vessel wallCirculation2010 12120332044

    Not in our library10.1161/circulationaha.109.895037

  292. 292.

    Missiou A Rudolf P Stachon P Wolf D Varo N Aichele P Colberg C Hoppe N Ernst S Munkel C TRAF5 deficiency accelerates atherogenesis in mice by increasing inflammatory cell recruitment and foam cell formationCirc Res2010 107757766

    Not in our library10.1161/circresaha.110.219295

  293. 293.

    Polykratis A van Loo G Xanthoulea S Hellmich M Pasparakis M Conditional targeting of tumor necrosis factor receptor-associated factor 6 reveals opposing functions of Toll-like receptor signaling in endothelial and myeloid cells in a mouse model of atherosclerosisCirculation2012 12617391751

    Not in our library10.1161/circulationaha.112.100339

  294. 294.

    Keats JJ Fonseca R Chesi M Schop R Baker A Chng WJ Van Wier S Tiedemann R Shi CX Sebag M Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myelomaCancer Cell2007 12131144

    Not in our library10.1016/j.ccr.2007.07.003

  295. 295.

    Annunziata CM Davis RE Demchenko Y Bellamy W Gabrea A Zhan F Lenz G Hanamura I Wright G Xiao W Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myelomaCancer Cell2007 12115130

    Not in our library10.1016/j.ccr.2007.07.004

  296. 296.

    Demchenko YN Glebov OK Zingone A Keats JJ Bergsagel PL Kuehl WM Classical and/or alternative NF-kappaB pathway activation in multiple myelomaBlood2010 11535413552

    Not in our library10.1182/blood-2009-09-243535

  297. 297.

    Du J Huo J Shi J Yuan Z Zhang C Fu W Jiang H Yi Q Hou J Polymorphisms of nuclear factor-kappaB family genes are associated with development of multiple myeloma and treatment outcome in patients receiving bortezomib-based regimensHaematologica2011 96729737

    Not in our library10.3324/haematol.2010.030577

  298. 298.

    Nagel I Bug S Tonnies H Ammerpohl O Richter J Vater I Callet-Bauchu E Calasanz MJ Martinez-Climent JA Bastard C Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del(14)(q24.1q32.33)Leukemia2009 2321532155

    Not in our library10.1038/leu.2009.149

  299. 299.

    Rossi D Deaglio S Dominguez-Sola D Rasi S Vaisitti T Agostinelli C Spina V Bruscaggin A Monti S Cerri M Alteration of BIRC3 and multiple other NF-{kappa}B pathway genes in splenic marginal zone lymphomaBlood2011 11849304934

    Not in our library10.1182/blood-2011-06-359166

  300. 300.

    Braggio E Keats JJ Leleu X Van Wier S Jimenez-Zepeda VH Valdez R Schop RF Price-Troska T Henderson K Sacco A Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemiaCancer Res2009 6935793588

    Not in our library10.1158/0008-5472.can-08-3701

  301. 301.

    Otto C Giefing M Massow A Vater I Gesk S Schlesner M Richter J Klapper W Hansmann ML Siebert R Genetic lesions of the TRAF3 and MAP3K14 genes in classical Hodgkin lymphomaBr J Haematol2012 157702708

    Not in our library10.1111/j.1365-2141.2012.09113.x

  302. 302.

    Compagno M Lim WK Grunn A Nandula SV Brahmachary M Shen Q Bertoni F Ponzoni M Scandurra M Califano A Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphomaNature2009 459717721

    Not in our library10.1038/nature07968

  303. 303.

    Cerhan JR Ansell SM Fredericksen ZS Kay NE Liebow M Call TG Dogan A Cunningham JM Wang AH Liu-Mares W Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphomaBlood2007 11044554463

    Not in our library10.1182/blood-2007-05-088682

  304. 304.

    Camilleri-Broet S Cremer I Marmey B Comperat E Viguie F Audouin J Rio MC Fridman WH Sautes-Fridman C Regnier CH TRAF4 overexpression is a common characteristic of human carcinomasOncogene2007 26142147

    Not in our library10.1038/sj.onc.1209762

  305. 305.

    Starczynowski DT Lockwood WW Delehouzee S Chari R Wegrzyn J Fuller M Tsao MS Lam S Gazdar AF Lam WL TRAF6 is an amplified oncogene bridging the RAS and NF-kappaB pathways in human lung cancerJ Clin Invest2011 12140954105

    Not in our library10.1172/jci58818

  306. 306.

    Meng Q Zheng M Liu H Song C Zhang W Yan J Qin L Liu X TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cellMol Cell Biochem2012 371177186

    Not in our library10.1007/s11010-012-1434-4

  307. 307.

    Lee YH Song GG Associations between TNFSF4 and TRAF1-C5 gene polymorphisms and systemic lupus erythematosus: a meta-analysisHum Immunol2012 7310501054

    Not in our library10.1016/j.humimm.2012.07.044

  308. 308.

    Kurreeman FA Goulielmos GN Alizadeh BZ Rueda B Houwing-Duistermaat J Sanchez E Bevova M Radstake TR Vonk MC Galanakis E The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseasesAnn Rheum Dis2010 69696699

    Not in our library10.1136/ard.2008.106567

  309. 309.

    Potter C Eyre S Cope A Worthington J Barton A Investigation of association between the TRAF family genes and RA susceptibilityAnn Rheum Dis2007 6613221326

    Not in our library10.1136/ard.2006.065706

  310. 310.

    Plenge RM Seielstad M Padyukov L Lee AT Remmers EF Ding B Liew A Khalili H Chandrasekaran A Davies LR TRAF1–C5 as a risk locus for rheumatoid arthritis–a genomewide studyN Engl J Med2007 35711991209

    Not in our library10.1056/nejmoa073491

  311. 311.

    Zervou MI Sidiropoulos P Petraki E Vazgiourakis V Krasoudaki E Raptopoulou A Kritikos H Choustoulaki E Boumpas DT Goulielmos GN Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous populationHum Immunol2008 69567571

    Not in our library10.1016/j.humimm.2008.06.006

  312. 312.

    Perez De Diego R Sancho-Shimizu V Lorenzo L Puel A Plancoulaine S Picard C Herman M Cardon A Durandy A Bustamante J Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitisImmunity2010 33400411

    Not in our library10.1016/j.immuni.2010.08.014

  313. 313.

    Fujikawa H Farooq M Fujimoto A Ito M Shimomura Y Functional studies for the TRAF6 mutation associated with hypohidrotic ectodermal dysplasiaBr J Dermatol2012

    Not in our library10.1111/bjd.12018

  314. 314.

    Durkop H Hirsch B Hahn C Foss HD Stein H Differential expression and function of A20 and TRAF1 in Hodgkin lymphoma and anaplastic large cell lymphoma and their induction by CD30 stimulationJ Pathol2003 200229239

    Not in our library10.1002/path.1351

  315. 315.

    Zapata JM Krajewska M Krajewski S Kitada S Welsh K Monks A McCloskey N Gordon J Kipps TJ Gascoyne RD TNFR-associated factor family protein expression in normal tissues and lymphoid malignanciesJ Immunol2000 16550845096

    Not in our library10.4049/jimmunol.165.9.5084

  316. 316.

    Munzert G Kirchner D Stobbe H Bergmann L Schmid RM Dohner H Heimpel H Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosisBlood2002 10037493756

    Not in our library10.1182/blood.v100.10.3749

  317. 317.

    Savage KJ Monti S Kutok JL Cattoretti G Neuberg D De Leval L Kurtin P Dal Cin P Ladd C Feuerhake F The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphomaBlood2003 10238713879

    Not in our library10.1182/blood-2003-06-1841

  318. 318.

    Bieche I Tomasetto C Regnier CH Moog-Lutz C Rio MC Lidereau R Two distinct amplified regions at 17q11-q21 involved in human primary breast cancerCancer Res1996 5638863890

    Not in our library

  319. 319.

    Krajewska M Krajewski S Zapata JM Van Arsdale T Gascoyne RD Berern K McFadden D Shabaik A Hugh J Reynolds A TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissuesAm J Pathol1998 15215491561

    Not in our library

  320. 320.

    Gu X Coates PJ MacCallum SF Boldrup L Sjostrom B Nylander K TRAF4 is potently induced by TAp63 isoforms and localised according to differentiation in SCCHNCancer Biol Ther2007 619861990

    Not in our library10.4161/cbt.6.12.5002

  321. 321.

    Rozan LM El-Deiry WS Identification and characterization of proteins interacting with Traf4, an enigmatic p53 targetCancer Biol Ther2006 512281235

    Not in our library10.4161/cbt.5.9.3295

  322. 322.

    Sax JK El-Deiry WS Identification and characterization of the cytoplasmic protein TRAF4 as a p53-regulated proapoptotic geneJ Biol Chem2003 2783643536444

    Not in our library10.1074/jbc.m303191200

  323. 323.

    Zhong L Cao F You Q Effect of TRAF6 on the biological behavior of human lung adenocarcinoma cellTumour Biol2013 34231239

    Not in our library10.1007/s13277-012-0543-8

  324. 324.

    Rajabi P Alaee M Mousavizadeh K Samadikuchaksaraei A Altered expression of TNFSF4 and TRAF2 mRNAs in peripheral blood mononuclear cells in patients with systemic lupus erythematosus: association with atherosclerotic symptoms and lupus nephritisInflamm Res2012 6113471354

    Not in our library10.1007/s00011-012-0535-6

  325. 325.

    Wisniewski SA Trzeciak WH A new mutation resulting in the truncation of the TRAF6-interacting domain of XEDAR: a possible novel cause of hypohidrotic ectodermal dysplasiaJ Med Genet2012 49499501

    Not in our library10.1136/jmedgenet-2012-100877

  326. 326.

    Zucchelli S Codrich M Marcuzzi F Pinto M Vilotti S Biagioli M Ferrer I Gustincich S TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson’s disease brainsHum Mol Genet2010 1937593770

    Not in our library10.1093/hmg/ddq290

  327. 327.

    Zucchelli S Marcuzzi F Codrich M Agostoni E Vilotti S Biagioli M Pinto M Carnemolla A Santoro C Gustincich S Tumor necrosis factor receptor-associated factor 6 (TRAF6) associates with huntingtin protein and promotes its atypical ubiquitination to enhance aggregate formationJ Biol Chem2011 2862510825117

    Not in our library10.1074/jbc.m110.187591

  328. 328.

    Bishop GA Xie P Multiple roles of TRAF3 signaling in lymphocyte functionImmunol Res2007 392232

    Not in our library10.1007/s12026-007-0068-1

  329. 329.

    Watts TH Lin GH Wang C McPherson AJ Snell LM Sabbagh L Role of 4-1BBL and TRAF1 in the CD8 T cell response to influenza virus and HIVAdv Exp Med Biol2011 691177186

    Not in our library10.1007/978-1-4419-6612-4_19

  330. 330.

    Snell LM Lin GH McPherson AJ Moraes TJ Watts TH T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapyImmunol Rev2011 244197217

    Not in our library10.1111/j.1600-065x.2011.01063.x

  331. 331.

    Wang C Watts TH Maintaining the balance: costimulatory TNFRs and control of HIVCytokine Growth Factor Rev2012 23245254

    Not in our library10.1016/j.cytogfr.2012.05.011

  332. 332.

    Wicovsky A Henkler F Salzmann S Scheurich P Kneitz C Wajant H Tumor necrosis factor receptor-associated factor-1 enhances proinflammatory TNF receptor-2 signaling and modifies TNFR1-TNFR2 cooperationOncogene2009 2817691781

    Not in our library10.1038/onc.2009.29

  333. 333.

    Wicovsky A Salzmann S Roos C Ehrenschwender M Rosenthal T Siegmund D Henkler F Gohlke F Kneitz C Wajant H TNF-like weak inducer of apoptosis inhibits proinflammatory TNF receptor-1 signalingCell Death Differ2009 1614451459

    Not in our library10.1038/cdd.2009.80

  334. 334.

    Ye H Arron JR Lamothe B Cirilli M Kobayashi T Shevde NK Segal D Dzivenu OK Vologodskaia M Yim M Distinct molecular mechanism for initiating TRAF6 signallingNature2002 418443447

    Not in our library10.1038/nature00888

  335. 335.

    Manna SK Babajan B Raghavendra PB Raviprakash N Sureshkumar C Inhibiting TRAF2-mediated activation of NF-kappaB facilitates induction of AP-1J Biol Chem2010 2851161711627

    Not in our library10.1074/jbc.m109.094961

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