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The Diverse Functional Roles of Elongation Factor Tu (EF-Tu) in Microbial Pathogenesis

Kate L. Harvey, Veronica M. Jarocki, Ian G. Charles and 1 more

Frontiers in Microbiology · 2019 · Review · CC BY

doi:10.3389/fmicb.2019.02351

Abstract

Elongation factor thermal unstable Tu (EF-Tu) is a G protein that catalyzes the binding of aminoacyl-tRNA to the A-site of the ribosome inside living cells. Structural and biochemical studies have described the complex interactions needed to effect canonical function. However, EF-Tu has evolved the capacity to execute diverse functions on the extracellular surface of both eukaryote and prokaryote cells. EF-Tu can traffic to, and is retained on, cell surfaces where can interact with membrane receptors and with extracellular matrix on the surface of plant and animal cells. Our structural studies indicate that short linear motifs (SLiMs) in surface exposed, non-conserved regions of the molecule may play a key role in the moonlighting functions ascribed to this ancient, highly abundant protein. Here we explore the diverse moonlighting functions relating to pathogenesis of EF-Tu in bacteria and examine putative SLiMs on surface-exposed regions of the molecule.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Elongation Factor Thermo Unstable (EF-Tu) is one the most abundant proteins found in bacteria, comprising up to 6% of the total protein expressed in Escherichia coli and as high as 10% of the total protein expressed in the genome reduced pathogen Mycoplasma pneumoniae. The primary, canonical function of EF-Tu is to transport aminoacylated tRNAs to the ribosome. Ef-Tu has been a therapeutic target for antibiotics (elfamycins) since the 1970s. However, current issues with elfamycins’ poor pharmacokinetics and solubility has prevented their commercialization as therapeutic agents.

Diverse functions have been ascribed to EF-Tu many of which include important virulence traits in Gram positive and Gram-negative pathogenic bacteria. To effect alternate virulence-associated functions, including adhesion to host extracellular matrix components, EF-Tu must gain access and be retained on the extracellular surface. This poses a challenge as signal secretion motifs are absent in this highly structured protein, and motifs required for binding diverse host cell surface receptor and matrix molecules must evolve without jeopardizing structural constraints needed to execute canonical function as a G protein. Here we refer to secondary functions as “moonlighting” functions. The concept of protein moonlighting is well established in eukaryotes, and is rapidly gaining traction in prokaryotes indicating that it is an ancient and evolutionally conserved phenomenon. Although EF-Tu executes various functions in eukaryotes, a review of the moonlighting roles of EF-Tu in bacteria is lacking. Therefore, this review has a focus to discuss the ever-expanding moonlighting roles of EF-Tu in prokaryotes, and how these roles relate to pathogenesis.

Structural Analysis of EF-Tu

Elongation factors (Table 1) in bacteria (e.g., EF-Tu also known as EF1A) and in eukaryotes (e.g., the eukaryotic Elongation Factor 1 Complex [eEF1A]) all have the same primary and critical function to shuttle aminoacylated tRNAs to the ribosome during protein translation. A codon–anticodon system ensures that the correct amino acid is added to the growing protein chain, a process that consumes guanosine triphosphate (GTP) prior to releasing the elongation factor from the aminoacyl tRNA. However, bacteria and eukaryotes differ in the mechanism by which they recharge the elongation factor/guanosine diphosphate (GDP) complex. This recharging function is executed by the Elongation Factor Thermo stable (EF-Ts) in prokaryotes and by eukaryotic Elongation Factor 1B (eEF1B) in eukaryotes (Figure 1).

EF-Tu is comprised of three domains known as domains i, ii and iii which have evolved a high degree of molecular flexibility. To perform its canonical function, EF-Tu must form a functional binding pocket for an aminoacyl-tRNA, and to achieve this, domain i must become aligned more closely to domains ii and iii (i.e., they must move by around 90°). The extent of intramolecular movement needed to accommodate the aminoacyl-tRNA is about one third of the protein’s total diameter, indicating how significant this conformational change is. Once the incoming aminoacyl-tRNA has docked with the mRNA, GTPase activity induces a reverse conformational change enabling the release of EF-Tu from the ribosome. The structural and functional constraints needed to execute these critical molecular interactions ensure that key domains within EF-Tu evolve slowly compared to molecules that perform their functions on the cell surface, where they face constant challenge from the host’s immunological defenses and undergo diversifying selection. As such, EF-Tu is considered to be an ancient molecule that is comprised of domains that are highly conserved in phylogenetically diverse prokaryotes. This sequence conservation extends to EF-Tu homologs in eukaryotes, which have also evolved a similar overall protein synthesis pathway.

Genetic Evolution of EF-Tu

In bacteria, EF-Tu is encoded by the tuf gene. tuf has a highly conserved genomic location and amino acid sequence, and has been used in the construction of phylogenetic trees for species discrimination. Amongst different bacterial species the EF-Tu sequences have less than 30% sequence divergence. Low G + C Gram positive bacteria carry only a single copy of tuf. In contrast, many enteric bacteria have two copies (tufA and tufB) while three tuf-like genes have been identified in Streptomyces ramocissimus. In species with two copies of the gene, the two genes differ by less than 1.4%, based on nucleotide comparison. In some bacteria with two copies of tuf, deletion of one copy of the gene is not lethal to the bacterium. It has been postulated that a second copy of this gene (which is mainly conserved in Gram negative bacteria) evolved before the branching of eubacteria. The cause for the intermittent presence of the second copy of tuf within eubacteria has been debated. It has been proposed that the second copy arose by lateral gene transfer, at least within Enterococci, whilst others argue that lateral gene transfer is unlikely in translation factors and attribute the discontinuous observation of a second tuf gene to the theory that it had been randomly lost in some lineages.

Eukaryotes have two isoforms of EF-Tu known as eEF1A1 and eEF1A2 (Table 1), with each sharing 96% amino acid similarity. Both isoforms are also highly expressed representing 1–11% of the total protein expressed. Some cells express just one of the eEF1A isoforms, while both are expressed after muscle trauma and in some tumor cell types. The number of genes encoding eEF1A varies widely within eukaryotes, from ten in maize to four in rice.

Moonlighting Proteins in Bacteria

There is now overwhelming evidence that proteins with canonical functions in the bacterial cytosol also perform important tasks on the bacterial cell surface. EF-Tu features prominently in many of these studies. Many moonlighting proteins are ancient, highly expressed enzymes, or are proteins that are perform essential roles in glycolysis, respiration and respond to stress. There is evidence that only a subset of cytosolic proteins can traffic onto the cell because other highly expressed cytosolic proteins are not observed on the cell surface or in extracellular secretions. Mass spectrometry studies have been instrumental in revealing the identities of surface accessible proteins that are not predicted to reside on the cell surface that have canonical functions in the bacterial cytosol. The presence of surface-associated moonlighting proteins has been confirmed using florescence and electron microscopy. It is notable that purified, soluble moonlighting protein fails to associate with the surface when exogenously incubated with bacterial cells suggesting that posttranslational modification(s) that occur in the host bacteria and/or passage through the cell membrane may be important events in a proteins ability to moonlight on the cell surface. Another unusual feature of protein moonlighting is that not all strains belonging to the same species present moonlighting proteins on their cell surface. For example, only a subset of pathogenic E. coli express surface GAPDH which binds host molecules. Finally, it is now known that moonlighting proteins are processed on the surface of bacterial pathogens. Processing is expected to increase protein disorder and alter function compared to the full length proteoform. Here we present key studies that describe the salient features that define the diverse moonlighting functions of EF-Tu related to pathogenesis (Figure 2 and Table 2).

EF-Tu Is Exposed on the Surface of Bacteria

EF-Tu was first described as having a moonlighting function on the cell surface of M. pneumoniae. As EF-Tu has now been found on the surface of a wide range of prokaryotes (Table 3), the potential mechanisms behind its extracellular locale shall be summarized here.

Typically, newly synthesized proteins destined for the cell surface possess either signal peptides or signal motifs that are recognized by transport machinery and translocated through the cytoplasmic membrane. However, conventionally cytosolic proteins lacking signal sequences, like EF-Tu, have also been identified extracellularly. These proteins, termed non-classically secreted proteins, can be differentiated from other cytosolic proteins by assessing properties such as amino acid composition and structurally disordered regions. Indeed, EF-Tu was one protein used to construct the feature-based non-classically secreted protein prediction software SecretomeP. However, the actual mechanisms behind non-classical protein secretion remain a topic for debate. While there are translocation systems that do not require signal peptides, such as the Holin–Antiholin system, ABC transporters, and a type seven secretion system in Gram-positive bacteria, these only account for a small portion of non-classically secreted proteins. Therefore, the presence of cytosolic proteins in extracellular locations is often linked with cell lysis.

There is evidence supporting cytosolic protein excretion through cell lysis, and there is evidence supporting excretion through alternative secretion pathways (reviewed in ). In addition to specific secretion pathways, cytosolic protein excretion can also occur through compromised membrane integrity, translational and osmotic stress, the protein’s biochemical and structural properties, and via membrane vesicles (MVs) (Outer Membrane Vesicles [OMVs] in Gram-negative bacteria) (reviewed in ).

Multiple mechanism may contribute to the surface location of EF-Tu; however, there are substantial reports of MVs carrying EF-Tu. Bacterial MVs are nanoparticles produced through processes such as membrane blebbing and endolysin-triggered cell death and contain various membrane and cytosolic proteins, as well as lipopolysaccharides, peptidoglycan and DNA. MVs are involved in diverse biological processes, including virulence, biofilm development, quorum sensing, horizontal gene transfer, and exportation of cellular components. EF-Tu is present within MVs derived from Gram-positive bacteria including Listeria monocytogenes, Mycobacterium bovis, Mycobacterium smegmatis, Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pnuemoniae, and Streptococcus pyogenes; Gram-negative bacteria including Acinetobacter baumannii, Bacteroides fragilis, Cronobacter sakazakii, Escherichia coli, Francisella novicida, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, and Pseudomonas aeruginosa; and in six Mycoplasma species. Indeed, EF-Tu was reported as one of the most abundant protein in some of these studies. Interestingly, several MVs that contain EF-Tu have been reported to increase virulence, modulate immune responses, and offer protection to infection via immunization. As the number of MV-encapsulated proteins varied dramatically within this subset of studies, ranging from 8 in S. agalactiae to 416 in F. novicida, it is not possible to determine the exact role EF-Tu plays in these processes in most instances. However, in the case of S. pneumoniae MVs, which were shown to have high immunogenic capacity and induce protective responses in mice, EF-Tu was one of 15/161 MV proteins that were immunogenic and one of two proteins from which antibodies were generated against in immunized mice.

EF-Tu Stimulates a Humoral Immune Response and Interacts With Host Immune Regulators

Antibodies against EF-Tu have also been detected in a range of natural infections, including those caused by Mycoplasma hyopneumoniae, Chlamydia trachomatis and K. pneumonia. Recombinant EF-Tu (rEF-Tu) from Mycoplasma ovipneumoniae induces an immune response in mice, increasing levels of IgG, TNF-α, IFN-γ, IL-12(p70), IL-4, IL-5, and IL-6. Sera from mice immunized with rEF-Tu also reduced M. ovipneumoniae growth. In Mycoplasma fermentans, EF-Tu interacts specifically with the C-terminal 34 amino acids of CD21 in human B lymphoma cells. CD21 receptors on the B cells enable the complement system to influence B-cell activation and maturation. The implication is that Mycoplasma species are involved in malignancies (reviewed in ) and the interaction between EF-Tu and CD21 may be significant in this regard. EF-Tu from L. monocytogenes is the main activator of host dendritic cells (DC), antigen presenting cells (APCs) that play a key role in host immune modulation. Activation of DCs is achieved when L. monocytogenes interacts with the pattern recognition receptors (PRRs) on the surface of DCs. These PRRs recognize bacterial proteins known as PAMPS (pathogen-associated molecular pattern). In L. monocytogenes EF-Tu was identified as a potent immuno-stimulatory effector in this process indicating that EF-Tu is a candidate for DC maturation-based therapies.

Recombinant EF-Tu (rEF-Tu) has recently shown promising results as a vaccine candidate against bacterial pathogens. Immunization with rEF-Tu elicited both Th1 and Th2-type responses against Streptococcus suis and anti-rEF-Tu sera reduced viable load detection in porcine blood. Mice immunized with rEF-Tu demonstrated significant protection against lethal challenges with S. pneumoniae and increased cytokine, IgG1 and IgG2a, and CD4+ T-cell production. rEF-Tu mediated protection against S. pneumoniae has also been demonstrated in fish, and partial protection against H. influenzae was achieved in mice.

Besides stimulating an immune response in mammals (Figure 2A), EF-Tu is also a recognized PAMP in plants. EF-Tu is secreted by via unknown mechanisms in soil dwelling, plant–pathogenic bacteria and is recognized by membrane-associated PRRs found on the extracellular surface of root epithelial cells in different plant species. The interaction between PRRs and PAMPS identifies the bacteria as an infectious threat, triggering a signal transduction cascade, that elicits an innate immune response that includes the production of reactive-oxygen species and programed cell death.

Both monocots and dicots use EF-Tu to notify their immune system of an infection. There is however, another level of sophistication to this interaction. Different plant species are known to have evolved recognition mechanisms in their respective PRRs that interact with different regions in the EF-Tu molecule. Rice PRRs recognize the amino acids (aa) 175-225 of EF-Tu, termed EFa50, from the plant pathogenic bacteria Acidovorax citrulli (formerly Acidovorax avenae) whereas Arabidopsis thaliana recognizes the first 18 aa of EF-Tu from E. coli (termed elf18). Although elf18 does not illicit a response to this pathogen in rice plants, engineering the Arabidopsis PRR for elf18 into the rice plant enabled rice to recognize elf18 and respond by increasing resistance to bacterial attack. This proof-of-concept experiment demonstrated that PRRs can to be engineered into the genomes of different crop species and may be beneficial to the farming and food production industry. Transfer of PRRs has already been demonstrated on food crops such as tomatoes and wheat. Earlier structural studies of EF-Tu suggested that the first 12 amino acids of EF-Tu are exposed on the surface and the dodecapeptide can act as a competitive inhibitor of the elf18 elicitor. The first 12aa of EF-Tu can also suppress the apoptotic response in plant cells allowing bacterial pathogens sufficient time and nutrient resources to colonize and replicate within plant cells. elf18 and EFa50 do not seem to have similar properties, but more recent structural studies have shown that they do appear to be (at least partially) surface exposed on the EF-Tu molecule. These data indicate that these two PAMPS can interact with PRRs on plant cell surfaces.

EF-Tu has also been shown to bind selectively to neuropeptide hormone substance P (SP). SP belongs to the tachykinin family of neuropeptides released by nerve and inflammatory cells and is linked to many inflammatory diseases because it binds to the neurokinin 1 receptor (NK-1R) which stimulates pro-inflammatory responses. The inability to trigger NK-1R decreases bacterial clearance and increases death rates in mouse models of infection. SP and/or NK-1R have been linked to disease caused by infectious agents, autoimmune disorders, psychological disturbances, cancer, atopic dermatitis, and cell proliferation. EF-Tu from S. aureus, S. epidermidis, and B. cereus has been shown to bind SP, with an associated increase in virulence and biofilm formation.

rEF-Tu derived from Lactobacillus johnsonii triggers a pro-inflammatory response in HT29 cells and increased IL-8 secretion in the presence of CD14. IL-8 is known to increase levels of calcium ions within the cell in which it is expressed. In Bacillus subtilis EF-Tu is a calcium binding protein. However, the link between calcium and EF-Tu in prokaryotes remains tenuous and further studies are needed to investigate the voracity of this association and its implication in the inflammatory response.

Infection

Adhesion to host cells and molecules is fundamental to pathogenesis in many bacterial species as it facilitates colonization, invasion, and host immune subversion. In many instances, moonlighting functions for EF-Tu are associated with a role in adherence to a range of host molecules and host cells (Figure 2B). This does not appear to be a trend in specific phylogenetic groups of prokaryotes, as it extends through a range of bacteria. EF-Tu resides on the surface of Francisella tularensis where it binds to the RGG domain of nucleolin on the surface of the human monocytic cell line THP-1. The HB-19 pseudopeptide irreversibly binds to the RGG domain in the C-terminus of nucleolin and effectively blocks attachment of Francisella tularensis. Consistent with these experiments, EF-Tu and a 32 kDa cleavage fragment of EF-Tu were recovered during affinity chromatography pull-down experiments using nucleolin as bait. It is notable that cleavage fragments of EF-Tu have been previously described in the cytoplasm and membrane fraction of L. monocytogenes and more recently on the extracellular surfaces of S. aureus, Mycoplasma hyopneumoniae and M. pneumoniae. Despite this finding, data describing the cleavage products in L. monocytogenes has not been reported but is an interesting observation nonetheless that warrants further investigation.

Fibronectin (Fn) is a key component of the extracellular matrix. It is a glycoprotein that binds to integrins embedded in eukaryote cell membranes and provides support and anchors cells to substrata. Many bacterial pathogens and commensals express adhesins that bind Fn and these interactions can trigger cytoskeletal rearrangements that promote host cell invasion. Interestingly, Fn also plays a role as a signaling molecule so, binding Fn may serve other functions for the bacteria, compounding their infectivity. Indeed, many bacteria have a repertoire of dedicated, secreted adhesins that target Fn.

EF-Tu localizes to both the outer membrane (OM) and outer membrane vesicles (OMV) of A. baumannii and binds to DsbA, a protein important in protein folding and maturation. In its external location in A. baumannii EF-Tu directly binds Fn. The genome-reduced, human pathogen, M. pneumoniae also displays EF-Tu on its cell surface and plays an important role in interactions with Fn. Anti-EF-Tu antibodies are able to prevent the binding of M. pneumoniae to immobilized Fn demonstrating the specificity of this interaction. Binding of EF-Tu is confined to the C-terminal region of EF-Tu, with two Fn-binding regions being identified at amino acid positions 192-292 and 314-394. The specificity of the Fn binding domain between amino acids 314-394 was confirmed when peptides spanning this region blocked the binding capacity of EF-Tu to Fn by 62%. Notably, EF-Tu from Mycoplasma genitalium, which shares 96% identity with EF-Tu from M. pneumoniae, does not bind Fn. Experimental comparison between the two sequences identified the residues S343, P345 and T357 to be key in the interaction with Fn. However, the Fn-binding A. baumannii EF-Tu does not possess these key binding residues identified in M. pneumoniae (see Supplementary File), suggesting an alternative Fn-binding mechanism. More recently, we have shown that EF-Tu from M. pneumoniae is a multifunctional, adhesive moonlighting protein that can bind fetuin, heparin, actin, as well as to plasminogen, vitronectin, lactoferrin, laminin, and fibrinogen.

The exogenous addition of soluble Fn is known to promote the ability of Mycobacterium avium subsp. paratuberculosis to attach and invade two epithelial cell lines but the identity of bacterial cell surface receptor(s) for Fn were not known. EF-Tu is a surface exposed cell wall protein in Mycobacterium avium subspecies paratuberculosis (MAP). With the importance of Fn to MAP adhesion and invasion, and as EF-Tu is known to bind Fn in M. pneumoniae and A. baumannii, it was investigated for its role as a Fn-binding protein. Knowledge of the Fn-binding regions of EF-Tu from M. pneumoniae was used to map putative Fn-binding regions in EF-Tu from A. baumannii. Although the two previously identified Fn-binding regions only showed 73 and 69% identity respectively in the EF-Tu homolog from MAP, ELISA assays showed that MAP EF-Tu binds Fn in a dose-dependent manner.

EF-Tu binds to human intestinal cells and mucins in a pH-dependent manner in the probiotic bacterium, Lactobacillus johnsonii suggesting a role for EF-Tu in gut colonization. At pH 5, EF-Tu derived from L. johnsonii was able to bind to the human colorectal adenocarcinoma cell line HT29 cells, undifferentiated CACO-2 cells and mucins isolated from HT29-MTX cells. The ability of EF-Tu to bind mucins extends to other anatomical locations, including the saliva mucin, MUC7. EF-Tu was identified as one of six proteins to bind this mucin in Streptococcus gordonii, a major oral colonizer.

When H. pylori is co-cultured with THP-1 cells, expression of EF-Tu is upregulated and secreted and shown to localize to the surface of the human monocytic cell line THP-1 implicating it in host adhesion.

While there are currently no universal moonlighting motifs, basic residues, both singularly and in clusters, are known to be binding anchors for anionic glycosaminoglycans, are key in plasminogen, DNA and actin-binding, and have been linked with biofilm formation. Such basic residue clusters are found throughout the sequences of EF-Tus with reported moonlighting functions (Figure 3 and Supplementary File).

A basic residue cluster is located at the N-termini of EF-Tu molecules with known moonlighting functions (Figure 3 and Table 2). This short linear motif (SLiM) has at least three surface exposed basic residues, resides within a region of protein disorder, and possesses predicted protein:protein interaction sites. The arginine and lysine residues in positions 7 and 9 are unconserved in some bacterial species, thus may have arisen from advantageous point mutations (Figure 4).

Interestingly, the moonlighting EF-Tu from Mycoplasma fermentans has a unique, highly surface exposed, N-terminal extension that is 39 amino acids in length and possess an additional basic residue cluster at 31nKmKgKy38 (see Supplementary File). Whether M. fermentans EF-Tu harbors moonlighting adhesive capabilities is currently unknown and may warrant future investigation.

Apart from the N-termini, the remaining basic residue clusters observed in EF-Tu molecules that moonlight are at least partially buried, which may impede their ability to bind host molecules. However selective cell surface proteolysis, described in detail in Section “Post-translational Modifications of EF-Tu,” can overcome some of the structural impediments.

EF-Tu Binds Innate Immune Effectors

Many bacterial pathogens of medical and veterinary significance have the ability to bind and activate plasminogen, a process that relies on interactions between basic amino acid residues on surface-accessible bacterial adhesins and kringle domains in plasminogen (Figure 2A). EF-Tu is also utilized by bacteria to dampen the host immune response. The ability of EF-Tu to bind to host complement factors and plasminogen has been demonstrated in Pseudomonas aeruginosa, Leptospira sp., Streptococcus pneumoniae M. pneumoniae (plasminogen only) and Acinetobacter baumannii (plasminogen only). The complement system is part of the innate immune system which non-specifically acts to clear the body of infection by lysing bacteria. Complement factors bound on the bacterial surface remain active, and plasminogen can be converted to plasmin in its bound state. This allows the bacteria to regulate and utilize these components for their own gain. By recruiting FH, FH1 and plasminogen the bacteria are able to inactivate C3b via a cleavage event mediated by FH, FH1 and plasmin. The C3b complement factor is an important opsonization trigger that binds and labels bacteria ready for opsonization by the host immune system. By degrading C3b, the bacteria are able to overcome this aspect of the innate immune system. Additionally, the recruitment of plasmin to the bacterial cell surface plays an important role in degrading ECM and facilitating tissue invasion. By binding complement factors such as Factor-H, FHL-1 and CFHR1 the bacterium is able to suppress this process and evade the host innate immune response.

Bacterial infections can also lead to a reduction in white blood cell (WBC) counts in infected hosts leading to leukopenia. Isolates of K. pneumoniae from patients with leukopenia express higher levels of EF-Tu compared with K. pneumoniae isolates from patients with leucocytosis suggesting that EF-Tu may be a pathogenicity factor in K. pneumonia-based leukopenia. Interestingly, EF-Tu is upregulated in Mycobacterium species that have been phagocytosed by macrophages. The purpose of this upregulation has yet to be determined, but may further support the idea of a role for EF-Tu in bacterial evasion of the host immune system.

Not only do bacteria have to defend themselves against the host immune response, but often they must defend themselves against each other. Due to the competitive environment in which bacteria live, they have developed toxins that target other bacterial cells. The Type VI secretion system (T6SS) can deliver toxin molecules into the cytosol of competing bacteria inhabiting the same niche. For the T6SS effector molecule in P. aeruginosa to enact its toxic effect, it must interact with EF-Tu prior to delivery into the recipient’s cytoplasm. The effector molecule and EF-Tu directly bind to each other in members of the Pseudomonas genus. These observations suggest that EF-Tu has a wide variety of moonlighting functions relating to pathogenesis in different prokaryote species.

Cell Shape

Some bacteria can change cell shape as a protective strategy against the immune system. By changing shape, bacteria can become less easily engulfed by phagocytes, and can enhance biofilm formation thereby increasing persistence in the host. Moreover, major actin-like cytoskeletal proteins, such as MreB, have a role in virulence. For example, in P. aeruginosa MreB regulates the type IV pili assemblage; in H. pylori MreB regulates the secretion of virulence factors; and in Salmonella enterica serovar Typhimurium a disruption in the mreB gene led to downregulation of genes involved in pathogenicity.

The hypothesis that EF-Tu may interact with the cytoskeleton in prokaryotes is not a new idea, with the concept being introduced as early as the 1970s when EF-Tu was shown to form filaments. More recently, the formation of amyloid-like filaments by Gallibacterium anatis EF-Tu has been linked to biofilm formation. EF-Tu also interacts with MreB in E. coli. MreB forms helical filaments beneath the cell membrane and is essential for regulating cell shape. As it is well known that eukaryotic EF-Tu (eEF1A) interacts with actin, and influences cell shape, it is conceivable that this moonlighting function also occurs in prokaryotes. In B. subtilis and E. coli, EF-Tu modulates the formation of MreB filaments by binding MreB in a ratio of 1:1 (Figure 2C). One hypothesis suggests a link between EF-Tu cell concentration and cytoskeletal function. By reducing the expression of EF-Tu in the cell, cell shape can be modulated from the typical rod-like appearance to an abnormal cell shape. Alteration of cell shape is due to disruption of the process that places MreB in helical structures beneath the membrane. Further studies investigated whether EF-Tu’s role in the translation mechanism was directly related to the population of EF-Tu molecules that interact with MreB, or whether separate populations of EF-Tu are generated for these alternate roles. Treatment of bacterial cells with kirromycin, which inhibits the release of EF-Tu from the ribosome, failed to interfere with EF-Tu localization in the cytoskeleton or its interactions with MreB filaments. As previous studies have only revealed an interaction between tufB with mreB (not tufA), it is tantalizing to consider whether only one of the tuf genes is responsible for the alternate function of cytoskeletal integrity. This might suggest that evolution of two tuf genes is useful in the delegation of EF-Tu moonlighting roles.

Post-translational Modifications of EF-Tu

Proteolytic processing is an irreversible post-translational modification (PTM) that can result in a loss, gain or change of function in a protein, as well as in degradation. Processing may be a mechanism to unlock moonlighting functions that are inherent in the newly created cleavage fragments via a mechanism similar to ectodomain shedding (Figure 2D). Furthermore, cleavage fragments may serve as competitive inhibitors to host immune cells. Host cytokines, chemokines, enzymes, antimicrobial peptides and growth factors all bind ECM components, including heparin and fibronectin, to control immune responses such as leukocyte emigration through tissue. By binding to the same ligands as host effector molecules, bacterial proteins and their cleavage fragments may dampen an immune response. Additionally, cleavage may result in the loss of antigenic epitopes in surface proteins thereby circumventing host immune detection.

Cell surface EF-Tu is proteolytically processed in M. hyopneumoniae. Cleavage fragments of EF-Tu are retained on the cell surface and recovered during affinity chromatography using different host molecules as bait. The cleavage of EF-Tu has recently been demonstrated to be more widespread than previously appreciated with cleavage sites now also mapped in the M. pneumoniae and S. aureus. Processing generates fragments that are predicted to be more structural disordered and exposes regions of EF-Tu that are normally inaccessible to the aqueous environment. In particular we have shown that novel SLiMs enriched in positive charges are exposed allowing them to bind to a range of host molecules. Processing has so far been described in bacteria that belong to the low G + C Firmicutes. Many protein:protein and protein:nucleic acid interactions require correctly spaced positive charges derived from lysine, arginine and histidine side chains in short regions of peptide sequence. Amino acids with positively charged side chain residues are encoded by A:T rich triplet codons and members of the low G + C Firmicutes are well suited to employ this as a strategy to expand their functional proteome. Single amino acid substitutions caused by single nucleotide polymorphisms (SNPs) have previously been described as pathogenicity-enhancing. Specifically, SNPs in E. coli and S. typhimurium adhesin genes have led to distinctive pathogenicity-enhanced phenotypes. SNPs can provide bacteria a selective advantage, leading to niche expansion and ultimately, novel species. We propose that the accumulation of positively charged residues via SNPs in SLiMs facilitates binding interactions with diverse host molecules. Processing presents a mechanism to release fragments, each with the potential to expose a different repertoire of SLiMS to the aqueous environment compared with the parent molecule, and generate protein multifunctionality.

Bacterial EF-Tus are also the target for reversible PTMs such as phosphorylation, methylation and acetylation. Phosphorylation of EF-Tu has been identified in E. coli, Thermus thermophiles, B. subtilis, Corynebacterium glutamicum, Streptomyces collinus, Thiobacillus ferrooxidans, S. pneumoniae, M. genitalium, and M. pneumoniae. While phosphorylation of EF-Tu lowers its binding affinity to GTP, subsequently reducing protein synthesis, the PTM also inhibits binding by the antibiotic kirromycin, a specific inhibitor of EF-Tu. Furthermore, the associated decreased bacterial growth facilitated by EF-Tu phosphorylation has been implicated as an acclimation measure to stress conditions during infection. Similarly, demonstrated that EF-Tu methylation in E. coli lowers GTP hydrolysis and suggest a more accurate translation process as a result.

Lysine acetylation and lysine glutarylation has been described in EF-Tu from Mycobacterium tuberculosis. These modifications can affect protein–protein and protein:nucleic acid interactions and it may be important to the pathogenicity of M. tuberculosis, although this is yet to be determined. Evidence for the role of PTMs in EF-Tu moonlighting functions have been described in P. aeruginosa, where the trimethylation of the lysine at residue 5, allows EF-Tu to structurally mimic phosphorylcholine. This modification means that EF-Tu can specifically bind a platelet-activating receptor, resulting in successful bacterial adhesion.

Concluding Remarks

EF-Tu has evolved to be a multifunctional protein in a wide variety of pathogenic bacteria. While moonlighting functions vary among microbial species there is a common theme for roles in adherence and in immune regulation. The understanding of how this essential and highly expressed protein evolved moonlighting functions is an active area of research and is likely that more diverse and important roles are yet to be discovered.

Author Contributions

KH and SD conceived and co-wrote the first draft with input from all authors for the final draft. VJ created the figures and contributed significantly to the revised manuscript. All authors contributed to revision, read and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Balasubramanian S. Kannan T. R. Hart P. J. Baseman J. B. (2009 ). Amino acid changes in elongation factor Tu of Mycoplasma pneumoniae and Mycoplasma genitalium influence fibronectin binding. Infect. Immun. 77 3533–3541.

    Not in our library10.1128/iai.00081-09

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    Balbo M. Barel M. Lottin-Divoux S. Jean D. Frade R. (2005 ). Infection of human B lymphoma cells by Mycoplasma fermentans induces interaction of its elongation factor with the intracytoplasmic domain of Epstein-Barr virus receptor (gp140, EBV/C3dR, CR2, CD21). FEMS Microbiol. Lett. 249 359–366.

    Not in our library10.1016/j.femsle.2005.06.052

  10. 10.

    Baldauf S. L. Palmer J. D. Doolittle W. F. (1996 ). The root of the universal tree and the origin of eukaryotes based on elongation factor phylogeny. Proc. Natl. Acad. Sci. U.S.A. 93 7749–7754.

    Not in our library10.1073/pnas.93.15.7749

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    Barbier M. Owings J. P. Martinez-Ramos I. Damron F. H. Gomila R. Blazquez J. (2013 ). Lysine trimethylation of EF-Tu mimics platelet-activating factor to initiate Pseudomonas aeruginosa pneumonia. mBio 4:e00207-13.

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  12. 12.

    Barel M. Hovanessian A. G. Meibom K. Briand J. P. Dupuis M. Charbit A. (2008 ). A novel receptor - ligand pathway for entry of Francisella tularensis in monocyte-like THP-1 cells: interaction between surface nucleolin and bacterial elongation factor Tu. BMC Microbiol. 8:145.

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  13. 13.

    Beck B. D. (1979 ). Polymerization of the bacterial elongation factor for protein synthesis, EF-Tu. Eur. J. Biochem. 97 495–502.

    Not in our library10.1111/j.1432-1033.1979.tb13137.x

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    Bendt A. K. Burkovski A. Schaffer S. Bott M. Farwick M. Hermann T. (2003 ). Towards a phosphoproteome map of Corynebacterium glutamicum. Proteomics 3 1637–1646.

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  15. 15.
    Non-classical protein secretion in bacteria · 2005
    No notice
  16. 16.

    Bergmann S. Rohde M. Chhatwal G. S. Hammerschmidt S. (2001 ). alpha-Enolase of Streptococcus pneumoniae is a plasmin(ogen)-binding protein displayed on the bacterial cell surface. Mol. Microbiol. 40 1273–1287.

    Not in our library10.1046/j.1365-2958.2001.02448.x

  17. 17.

    Berry I. J. Jarocki V. M. Tacchi J. L. Raymond B. B. A. Widjaja M. Padula M. P. (2017 ). N-terminomics identifies widespread endoproteolysis and novel methionine excision in a genome-reduced bacterial pathogen. Sci. Rep. 7:11063.

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    Bhattacharya S. Ploplis V. A. Castellino F. J. (2012 ). Bacterial plasminogen receptors utilize host plasminogen system for effective invasion and dissemination. J. Biomed. Biotechnol. 2012:482096.

    Not in our library10.1155/2012/482096

  19. 19.

    Bingham R. Ekunwe S. I. Falk S. Snyder L. Kleanthous C. (2000 ). The major head protein of bacteriophage T4 binds specifically to elongation factor Tu. J. Biol. Chem. 275 23219–23226.

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    Boddicker J. D. Ledeboer N. A. Jagnow J. Jones B. D. Clegg S. (2002 ). Differential binding to and biofilm formation on, HEp-2 cells by Salmonella enterica serovar typhimurium is dependent upon allelic variation in the fimH gene of the fim gene cluster. Mol. Microbiol. 45 1255–1265.

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  21. 21.

    Bogema D. R. Deutscher A. T. Woolley L. K. Seymour L. M. Raymond B. B. A. Tacchi J. L. (2012 ). Characterization of cleavage events in the multifunctional cilium adhesin Mhp684 (P146) reveals a mechanism by which Mycoplasma hyopneumoniae regulates surface topography. mBio 3:e00282-11.

    Not in our library10.1128/mbio.00282-11

  22. 22.

    Bosutti A. Scaggiante B. Grassi G. Guarnieri G. Biolo G. (2007 ). Overexpression of the elongation factor 1A1 relates to muscle proteolysis and proapoptotic p66(ShcA) gene transcription in hypercatabolic trauma patients. Metabolism 56 1629–1634.

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  23. 23.

    Boysen A. Borch J. Krogh T. J. Hjerno K. Moller-Jensen J. (2015 ). SILAC-based comparative analysis of pathogenic Escherichia coli secretomes. J. Microbiol. Methods 116 66–79.

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    Bulmer D. M. Kharraz L. Grant A. J. Dean P. Morgan F. J. E. Karavolos M. H. (2012 ). The bacterial cytoskeleton modulates motility, type 3 secretion, and colonization in Salmonella. PLoS Pathog. 8:e1002500.

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  25. 25.

    Burtnick M. N. Brett P. J. DeShazer D. (2014 ). Proteomic analysis of the Burkholderia pseudomallei type II secretome reveals hydrolytic enzymes, novel proteins, and the deubiquitinase TssM. Infect. Immun. 82 3214–3226.

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    Butland G. Peregrin-Alvarez J. M. Li J. Yang W. Yang X. Canadien V. (2005 ). Interaction network containing conserved and essential protein complexes in Escherichia coli. Nature 433 531–537.

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    Caamano-Antelo S. Fernandez-No I. C. Bohme K. Ezzat-Alnakip M. Quintela-Baluja M. Barros-Velazquez J. (2015 ). Genetic discrimination of foodborne pathogenic and spoilage Bacillus spp. based on three housekeeping genes. Food Microbiol. 46 288–298.

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  28. 28.

    Cacan E. Kratzer J. T. Cole M. F. Gaucher E. A. (2013 ). Interchanging functionality among homologous elongation factors using signatures of heterotachy. J. Mol. Evol. 76 4–12.

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  29. 29.

    Candela M. Centanni M. Fiori J. Biagi E. Turroni S. Orrico C. (2010 ). DnaK from Bifidobacterium animalis subsp. Lactis is a surface-exposed human plasminogen receptor upregulated in response to bile salts. Microbiology 156 1609–1618.

    Not in our library10.1099/mic.0.038307-0

  30. 30.

    Cao Y. Bazemore-Walker C. R. (2014 ). Proteomic profiling of the surface-exposed cell envelope proteins of Caulobacter crescentus. J. Proteomics 97 187–194.

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  31. 31.

    Carpenter L. L. Bayat L. Moreno F. Kling M. A. Price L. H. Tyrka A. R. (2008 ). Decreased cerebrospinal fluid concentrations of substance P in treatment-resistant depression and lack of alteration after acute adjunct vagus nerve stimulation therapy. Psychiatry Res. 157 123–129.

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  32. 32.

    Carrasco S. E. Yang Y. Troxell B. Yang X. Pal U. Yang X. F. (2015 ). Borrelia burgdorferi elongation factor EF-Tu is an immunogenic protein during Lyme borreliosis. Emerg. Microbes Infect. 4:e54.

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    Chande A. G. Siddiqui Z. Midha M. K. Sirohi V. Ravichandran S. Rao K. V. (2015 ). Selective enrichment of mycobacterial proteins from infected host macrophages. Sci. Rep. 5:13430.

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  34. 34.

    Chiu K. H. Wang L. H. Tsai T. T. Lei H. Y. Liao P. C. (2016 ). Secretomic analysis of host-pathogen interactions reveals that elongation Factor-Tu is a potential adherence factor of Helicobacter pylori during pathogenesis. J. Proteome Res. 16 264–273.

    Not in our library10.1021/acs.jproteome.6b00584

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    Choi D. S. Kim D. K. Choi S. J. Lee J. Choi J. P. Rho S. (2011 ). Proteomic analysis of outer membrane vesicles derived from Pseudomonas aeruginosa. Proteomics 11 3424–3429.

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  36. 36.

    Christie-Oleza J. A. Armengaud J. Guerin P. Scanlan D. J. (2015a ). Functional distinctness in the exoproteomes of marine Synechococcus. Env. Microbiol. 17 3781–3794.

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  37. 37.

    Christie-Oleza J. A. Scanlan D. J. Armengaud J. (2015b ). “You produce while I clean up”, a strategy revealed by exoproteomics during Synechococcus-Roseobacter interactions. Proteomics 15 3454–3462.

    Not in our library10.1002/pmic.201400562

  38. 38.

    Chung M.-C. Tonry J. H. Narayanan A. Manes N. P. Mackie R. S. Gutting B. (2011 ). Bacillus anthracis interacts with plasmin(ogen) to evade C3b-dependent innate immunity. PLoS One 6:e18119.

    Not in our library10.1371/journal.pone.0018119

  39. 39.

    Churchward C. P. Rosales R. S. Gielbert A. Dominguez M. Nicholas R. A. Ayling R. D. (2015 ). Immunoproteomic characterisation of Mycoplasma mycoides subspecies capri by mass spectrometry analysis of two-dimensional electrophoresis spots and western blot. J. Pharm. Pharmacol. 67 364–371.

    Not in our library10.1111/jphp.12344

  40. 40.

    Cianfanelli F. R. Monlezun L. Coulthurst S. J. (2016 ). Aim, load, fire: the type VI secretion system, a bacterial nanoweapon. Trends Microbiol. 24 51–62.

    Not in our library10.1016/j.tim.2015.10.005

  41. 41.

    Clair G. Lorphelin A. Armengaud J. Duport C. (2013 ). OhrRA functions as a redox-responsive system controlling toxinogenesis in Bacillus cereus. J. Proteomics 94 527–539.

    Not in our library10.1016/j.jprot.2013.10.024

  42. 42.

    Coelho C. Brown L. Maryam M. Vij R. Smith D. F. Q. Burnet M. C. (2019 ). Listeria monocytogenes virulence factors, including listeriolysin O, are secreted in biologically active extracellular vesicles. J. Biol. Chem. 294 1202–1217.

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  43. 43.

    Coulthurst S. J. (2013 ). The type VI secretion system - a widespread and versatile cell targeting system. Res. Microbiol. 164 640–654.

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  44. 44.

    Cowles K. N. Gitai Z. (2010 ). Surface association and the MreB cytoskeleton regulate pilus production, localization and function in Pseudomonas aeruginosa. Mol. Microbiol. 76 1411–1426.

    Not in our library10.1111/j.1365-2958.2010.07132.x

  45. 45.

    Dalla Vecchia E. Shao P. P. Suvorova E. Chiappe D. Hamelin R. Bernier-Latmani R. (2014 ). Characterization of the surfaceome of the metal-reducing bacterium Desulfotomaculum reducens. Front. Microbiol. 5:432.

    Not in our library10.3389/fmicb.2014.00432

  46. 46.

    Dallo S. F. Kannan T. R. Blaylock M. W. Baseman J. B. (2002 ). Elongation factor Tu and E1 beta subunit of pyruvate dehydrogenase complex act as fibronectin binding proteins in Mycoplasma pneumoniae. Mol. Microbiol. 46 1041–1051.

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  47. 47.

    Dallo S. F. Zhang B. Denno J. Hong S. Tsai A. Haskins W. (2012 ). Association of Acinetobacter baumannii EF-Tu with cell surface, outer membrane vesicles, and fibronectin. ScientificWorldJournal 2012:128705.

    Not in our library10.1100/2012/128705

  48. 48.

    Datar P. Srivastava S. Coutinho E. Govil G. (2004 ). Substance P: structure, function, and therapeutics. Curr. Top. Med. Chem 4 75–103.

    Not in our library10.2174/1568026043451636

  49. 49.

    Defeu Soufo H. J. Reimold C. Breddermann H. Mannherz H. G. Graumann P. L. (2015 ). Translation elongation factor EF-Tu modulates filament formation of actin-like MreB protein in vitro. J. Mol. Biol. 427 1715–1727.

    Not in our library10.1016/j.jmb.2015.01.025

  50. 50.

    Defeu Soufo H. J. Reimold C. Linne U. Knust T. Gescher J. Graumann P. L. (2010 ). Bacterial translation elongation factor EF-Tu interacts and colocalizes with actin-like MreB protein. Proc. Natl. Acad. Sci. U.S.A. 107 3163–3168.

    Not in our library10.1073/pnas.0911979107

  51. 51.

    Deutscher A. T. Jenkins C. Minion F. C. Seymour L. M. Padula M. P. Dixon N. E. (2010 ). Repeat regions R1 and R2 in the P97 paralogue Mhp271 of Mycoplasma hyopneumoniae bind heparin, fibronectin and porcine cilia. Mol. Microbiol. 78 444–458.

    Not in our library10.1111/j.1365-2958.2010.07345.x

  52. 52.

    Dhanani A. S. Bagchi T. (2013 ). The expression of adhesin EF-Tu in response to mucin and its role in Lactobacillus adhesion and competitive inhibition of enteropathogens to mucin. J. Appl. Microbiol. 115 546–554.

    Not in our library10.1111/jam.12249

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    Dhanani A. S. Gaudana S. B. Bagchi T. (2011 ). The ability of Lactobacillus adhesin EF-Tu to interfere with pathogen adhesion. Eur. Food Res. Technol. 232 777–785.

    Not in our library10.1007/s00217-011-1443-7

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    Doble A. C. Bulmer D. M. Kharraz L. Karavolos M. H. Khan C. M. A. (2012 ). The function of the bacterial cytoskeleton in Salmonella pathogenesis. Virulence 3 446–449.

    Not in our library10.4161/viru.20993

  55. 55.

    Dominguez D. C. Lopes R. Palomino J. (2009 ). B. subtilis elongation factor Tu binds Calcium ions. FASEB J. 23:LB211.

    Not in our library

  56. 56.

    Douglas S. D. Ho W. Z. Gettes D. R. Cnaan A. Zhao H. Leserman J. (2001 ). Elevated substance P levels in HIV-infected men. AIDS 15 2043–2045.

    Not in our library10.1097/00002030-200110190-00019

  57. 57.

    Ebner K. Singewald N. (2006 ). The role of substance P in stress and anxiety responses. Amino Acids 31 251–272.

    Not in our library10.1007/s00726-006-0335-9

  58. 58.

    Ebner P. Götz F. (2019 ). Bacterial excretion of cytoplasmic proteins (ECP): occurrence, mechanism, and function. Trends Microbiol. 27 176–187.

    Not in our library10.1016/j.tim.2018.10.006

  59. 59.

    Egea L. Aguilera L. Gimenez R. Sorolla M. A. Aguilar J. Badia J. (2007 ). Role of secreted glyceraldehyde-3-phosphate dehydrogenase in the infection mechanism of enterohemorrhagic and enteropathogenic Escherichia coli: interaction of the extracellular enzyme with human plasminogen and fibrinogen. Int. J. Biochem. Cell Biol. 39 1190–1203.

    Not in our library10.1016/j.biocel.2007.03.008

  60. 60.

    Ejiri S. (2002 ). Moonlighting functions of polypeptide elongation factor 1: from actin bundling to zinc finger protein R1-associated nuclear localization. Biosci. Biotechnol. Biochem. 66 1–21.

    Not in our library10.1271/bbb.66.1

  61. 61.

    Eshghi A. Henderson J. Trent M. S. Picardeau M. (2015 ). Leptospira interrogans lpxD homologue is required for thermal acclimatization and virulence. Infect. Immun. 83 4314–4321.

    Not in our library10.1128/iai.00897-15

  62. 62.

    Espino E. Koskenniemi K. Mato-Rodriguez L. Nyman T. A. Reunanen J. Koponen J. (2015 ). Uncovering surface-exposed antigens of Lactobacillus rhamnosus by cell shaving proteomics and two-dimensional immunoblotting. J. Proteome Res. 14 1010–1024.

    Not in our library10.1021/pr501041a

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    Esteban F. Munoz M. Gonzalez-Moles M. A. Rosso M. (2006 ). A role for substance P in cancer promotion and progression: a mechanism to counteract intracellular death signals following oncogene activation or DNA damage. Cancer Metastasis Rev. 25 137–145.

    Not in our library10.1007/s10555-006-8161-9

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    Fehder W. P. Sachs J. Uvaydova M. Douglas S. D. (1997 ). Substance P as an immune modulator of anxiety. Neuroimmunomodulation 4 42–48.

    Not in our library10.1159/000097314

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    Feng L. Niu X. Mei W. Li W. Liu Y. Willias S. P. (2018 ). Immunogenicity and protective capacity of EF-Tu and FtsZ of Streptococcus suis serotype 2 against lethal infection. Vaccine 36 2581–2588.

    Not in our library10.1016/j.vaccine.2018.03.079

  66. 66.

    Ferreira R. M. Moreira L. M. Ferro J. A. Soares M. R. Laia M. L. Varani A. M. (2016 ). Unravelling potential virulence factor candidates in Xanthomonas citri. subsp. citri by secretome analysis. PeerJ 4:e1734.

    Not in our library10.7717/peerj.1734

  67. 67.

    Filer D. Furano A. V. (1980 ). Portions of the gene encoding elongation factor Tu are highly conserved in prokaryotes. J. Biol. Chem. 255 728–734.

    Not in our library

  68. 68.

    Filer D. Furano A. V. (1981 ). Duplication of the tuf gene, which encodes peptide chain elongation factor Tu, is widespread in Gram-negative bacteria. J. Bacteriol. 148 1006–1011.

    Not in our library10.1128/jb.148.3.1006-1011.1981

  69. 69.

    Furano A. V. (1975 ). Content of elongation factor Tu in Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 72 4780–4784.

    Not in our library10.1073/pnas.72.12.4780

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    Two Distinct EF-Tu Epitopes Induce Immune Responses in Rice and Arabidopsis · 2014
    Not checked
  71. 71.
    Mycoplasmas are no exception to extracellular vesicles release: Revisiting old concepts. · 2018
    Not checked
  72. 72.
    Specific peptide-activated proteolytic cleavage of Escherichia coli elongation factor Tu · 1998
    Not checked
  73. 73.

    Gill S. Wight T. N. Frevert C. W. (2010 ). Proteoglycans: key regulators of pulmonary inflammation and the innate immune response to lung infection. Anat. Rec. Hoboken N. J. 2007 968–981.

    Not in our library10.1002/ar.21094

  74. 74.

    Goode T. O’Connor T. Hopkins A. Moriarty D. O’Sullivan G. C. Collins J. K. (2003 ). Neurokinin-1 receptor (NK-1R) expression is induced in human colonic epithelial cells by proinflammatory cytokines and mediates proliferation in response to substance P. J. Cell. Physiol. 197 30–41.

    Not in our library10.1002/jcp.10234

  75. 75.

    Götz F. Yu W. Dube L. Prax M. Ebner P. (2015 ). Excretion of cytosolic proteins (ECP) in bacteria. Int. J. Med. Microbiol. 305 230–237.

    Not in our library10.1016/j.ijmm.2014.12.021

  76. 76.

    Granato D. Bergonzelli G. E. Pridmore R. D. Marvin L. Rouvet M. Corthesy-Theulaz I. E. (2004 ). Cell surface-associated elongation factor Tu mediates the attachment of Lactobacillus johnsonii NCC533 (La1) to human intestinal cells and mucins. Infect. Immun. 72 2160–2169.

    Not in our library10.1128/iai.72.4.2160-2169.2004

  77. 77.

    Green E. Mecsas J. (2016 ). Bacterial secretion systems: an overview, in: Virulence Mechanisms of Bacterial Pathogens. Washington, DC: ASM Press, 215–240.

    Not in our library

  78. 78.

    Green J. V. Orsborn K. I. Zhang M. Tan Q. K. G. Greis K. D. Porollo A. (2013 ). Heparin-binding motifs and biofilm formation by Candida albicans. J. Infect. Dis. 208 1695–1704.

    Not in our library10.1093/infdis/jit391

  79. 79.

    Grundel A. Friedrich K. Pfeiffer M. Jacobs E. Dumke R. (2015 ). Subunits of the pyruvate dehydrogenase cluster of Mycoplasma pneumoniae are surface-displayed proteins that bind and activate human plasminogen. PLoS One 10:e0126600.

    Not in our library10.1371/journal.pone.0126600

  80. 80.

    He Y. Wang H. Chen L. (2015 ). Comparative secretomics reveals novel virulence-associated factors of Vibrio parahaemolyticus. Front. Microbiol. 6:707.

    Not in our library10.3389/fmicb.2015.00707

  81. 81.

    Henderson B. Martin A. (2011 ). Bacterial virulence in the moonlight: multitasking bacterial moonlighting proteins are virulence determinants in infectious disease. Infect. Immun. 79 3476–3491.

    Not in our library10.1128/iai.00179-11

  82. 82.

    Henderson B. Martin A. (2013 ). Bacterial moonlighting proteins and bacterial virulence. Curr. Top. Microbiol. Immunol. 358 155–213.

    Not in our library10.1007/82_2011_188

  83. 83.

    Henderson B. Nair S. Pallas J. Williams M. A. (2011 ). Fibronectin: a multidomain host adhesin targeted by bacterial fibronectin-binding proteins. FEMS Microbiol. Rev. 35 147–200.

    Not in our library10.1111/j.1574-6976.2010.00243.x

  84. 84.

    Heras B. Shouldice S. R. Totsika M. Scanlon M. J. Schembri M. A. Martin J. L. (2009 ). DSB proteins and bacterial pathogenicity. Nat. Rev. Microbiol. 7 215–225.

    Not in our library10.1038/nrmicro2087

  85. 85.

    Herpfer I. Lieb K. (2005 ). Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs 19 275–293.

    Not in our library10.2165/00023210-200519040-00001

  86. 86.

    Huberts D. H. E. W. van der Klei I. J. (2010 ). Moonlighting proteins: An intriguing mode of multitasking. Biochim. Biophys. Acta 1803 520–525.

    Not in our library10.1016/j.bbamcr.2010.01.022

  87. 87.

    Hughes D. (1990 ). Both genes for EF-Tu in Salmonella typhimurium are individually dispensable for growth. J. Mol. Biol. 215 41–51.

    Not in our library10.1016/s0022-2836(05)80093-2

  88. 88.

    Igarashi D. Bethke G. Xu Y. Tsuda K. Glazebrook J. Katagiri F. (2013 ). Pattern-triggered immunity suppresses programmed cell death triggered by fumonisin b1. PLoS One 8:e60769.

    Not in our library10.1371/journal.pone.0060769

  89. 89.

    Iwabe N. Kuma K. Hasegawa M. Osawa S. Miyata T. (1989 ). Evolutionary relationship of archaebacteria, eubacteria, and eukaryotes inferred from phylogenetic trees of duplicated genes. Proc. Natl. Acad. Sci. U.S.A. 86 9355–9359.

    Not in our library10.1073/pnas.86.23.9355

  90. 90.

    Jain S. Kumar S. Dohre S. Afley P. Sengupta N. Alam S. I. (2014 ). Identification of a protective protein from stationary-phase exoproteome of Brucella abortus. Pathog. Dis. 70 75–83.

    Not in our library10.1111/2049-632x.12079

  91. 91.
    MHJ_0461 is a multifunctional leucine aminopeptidase on the surface of Mycoplasma hyopneumoniae · 2015
    Not checked
  92. 92.

    Jayaraman G. Wu C. W. Liu Y. J. Chien K. Y. Fang J. C. Lyu P. C. (2000 ). Binding of a de novo designed peptide to specific glycosaminoglycans. FEBS Lett. 482 154–158.

    Not in our library10.1016/s0014-5793(00)01964-5

  93. 93.

    Jeffery C. J. (1999 ). Moonlighting proteins. Trends Biochem. Sci. 24 8–11.

    Not in our library10.1016/s0968-0004(98)01335-8

  94. 94.

    Jeffery C. J. (2005 ). Mass spectrometry and the search for moonlighting proteins. Mass Spectrom. Rev. 24 772–782.

    Not in our library10.1002/mas.20041

  95. 95.

    Jeffery C. J. (2018 ). Protein moonlighting: what is it, and why is it important? Philos. Trans. R. Soc. Lond. B. Biol. Sci. 373:20160523.

    Not in our library10.1098/rstb.2016.0523

  96. 96.
    Elongation Factor Tu and Heat Shock Protein 70 Are Membrane-Associated Proteins from Mycoplasma ovipneumoniae Capable of Inducing Strong Immune Response in Mice. · 2016
    Not checked
  97. 97.

    Jimenez-Munguia I. van Wamel W. J. Olaya-Abril A. Garcia-Cabrera E. Rodriguez-Ortega M. J. Obando I. (2015 ). Proteomics-driven design of a multiplex bead-based platform to assess natural IgG antibodies to pneumococcal protein antigens in children. J. Proteomics 126 228–233.

    Not in our library10.1016/j.jprot.2015.06.011

  98. 98.

    Jones L. J. Carballido-Lopez R. Errington J. (2001 ). Control of cell shape in bacteria: helical, actin-like filaments in Bacillus subtilis. Cell 104 913–922.

    Not in our library10.1016/s0092-8674(01)00287-2

  99. 99.
    Dancing to Another Tune—Adhesive Moonlighting Proteins in Bacteria · 2014
    No notice
  100. 100.

    Kaneider N. C. Djanani A. Wiedermann C. J. (2007 ). Heparan sulfate proteoglycan-involving immunomodulation by cathelicidin antimicrobial peptides LL-37 and PR-39. ScientificWorldJournal 7 1832–1838.

    Not in our library10.1100/tsw.2007.285

  101. 101.

    Ke D. Boissinot M. Huletsky A. Picard F. J. Frenette J. Ouellette M. (2000 ). Evidence for horizontal gene transfer in evolution of elongation factor Tu in enterococci. J. Bacteriol. 182 6913–6920.

    Not in our library10.1128/jb.182.24.6913-6920.2000

  102. 102.

    Kesimer M. Kilic N. Mehrotra R. Thornton D. J. Sheehan J. K. (2009 ). Identification of salivary mucin MUC7 binding proteins from Streptococcus gordonii. BMC Microbiol. 9:163.

    Not in our library10.1186/1471-2180-9-163

  103. 103.

    Kim S. K. Park M. K. Kim S. H. Oh K. G. Jung K. H. Hong C. H. (2014 ). Identification of stringent response-related and potential serological proteins released from Bacillus anthracis overexpressing the RelA/SpoT homolog, Rsh Bant. Curr. Microbiol. 69 436–444.

    Not in our library10.1007/s00284-014-0606-8

  104. 104.

    Kjeldgaard M. Nissen P. Thirup S. Nyborg J. (1993 ). The crystal structure of elongation factor EF-Tu from Thermus aquaticus in the GTP conformation. Structure 1 35–50.

    Not in our library10.1016/0969-2126(93)90007-4

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    Kloppot P. Selle M. Kohler C. Stentzel S. Fuchs S. Liebscher V. (2015 ). Microarray-based identification of human antibodies against Staphylococcus aureus antigens. Proteomics Clin. Appl. 9 1003–1011.

    Not in our library10.1002/prca.201400123

  106. 106.

    Koenigs A. Zipfel P. F. Kraiczy P. (2015 ). Translation elongation factor Tuf of Acinetobacter baumannii is a plasminogen-binding protein. PLoS One 10:e0134418.

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  107. 107.

    Komeil D. Padilla-Reynaud R. Lerat S. Simao-Beaunoir A. M. Beaulieu C. (2014 ). Comparative secretome analysis of Streptomyces scabiei during growth in the presence or absence of potato suberin. Proteome Sci. 12:35.

    Not in our library10.1186/1477-5956-12-35

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    Krachler A. M. Orth K. (2013 ). Targeting the bacteria-host interface: strategies in anti-adhesion therapy. Virulence 4 284–294.

    Not in our library10.4161/viru.24606

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    Kudva I. T. Krastins B. Torres A. G. Griffin R. W. Sheng H. Sarracino D. A. (2015 ). The Escherichia coli O157:H7 cattle immunoproteome includes outer membrane protein A (OmpA), a modulator of adherence to bovine rectoanal junction squamous epithelial (RSE) cells. Proteomics 15 1829–1842.

    Not in our library10.1002/pmic.201400432

  110. 110.

    Kunert A. Losse J. Gruszin C. Huhn M. Kaendler K. Mikkat S. (2007 ). Immune evasion of the human pathogen Pseudomonas aeruginosa: elongation factor Tuf is a factor H and plasminogen binding protein. J. Immunol. 179 2979–2988.

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  111. 111.

    Kunze G. Zipfel C. Robatzek S. Niehaus K. Boller T. Felix G. (2004 ). The N terminus of bacterial elongation factor Tu elicits innate immunity in Arabidopsis plants. Plant Cell 16 3496–3507.

    Not in our library10.1105/tpc.104.026765

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    Kwon S.-O. Gho Y. S. Lee J. C. Kim S. I. (2009 ). Proteome analysis of outer membrane vesicles from a clinical Acinetobacter baumannii isolate. FEMS Microbiol. Lett. 297 150–156.

    Not in our library10.1111/j.1574-6968.2009.01669.x

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    Lacombe S. Rougon-Cardoso A. Sherwood E. Peeters N. Dahlbeck D. van Esse H. P. (2010 ). Interfamily transfer of a plant pattern-recognition receptor confers broad-spectrum bacterial resistance. Nat. Biotechnol. 28 365–369.

    Not in our library10.1038/nbt.1613

  114. 114.

    Lahteenmaki K. Kuusela P. Korhonen T. K. (2000 ). Plasminogen activation in degradation and penetration of extracellular matrices and basement membranes by invasive bacteria. Methods 21 125–132.

    Not in our library10.1006/meth.2000.0983

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    Lambris J. D. Ricklin D. Geisbrecht B. V. (2008 ). Complement evasion by human pathogens. Nat. Rev. Microbiol. 6 132–142.

    Not in our library10.1038/nrmicro1824

  116. 116.
    Proteomic evidences for rex regulation of metabolism in toxin-producing Bacillus cereus ATCC 14579. · 2014
    Not checked
  117. 117.

    Lathe W. C. Bork P. (2001 ). Evolution of tuf genes: ancient duplication, differential loss and gene conversion. FEBS Lett. 502 113–116.

    Not in our library10.1016/s0014-5793(01)02639-4

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    Le Marechal C. Peton V. Ple C. Vroland C. Jardin J. Briard-Bion V. (2015 ). Surface proteins of Propionibacterium freudenreichii are involved in its anti-inflammatory properties. J Proteomics 113 447–461.

    Not in our library10.1016/j.jprot.2014.07.018

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    Lecomte X. Gagnaire V. Briard-Bion V. Jardin J. Lortal S. Dary A. (2014 ). The naturally competent strain Streptococcus thermophilus LMD-9 as a new tool to anchor heterologous proteins on the cell surface. Microb. Cell Fact. 13:82.

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    Lee E.-Y. Bang J. Y. Park G. W. Choi D.-S. Kang J. S. Kim H.-J. (2007 ). Global proteomic profiling of native outer membrane vesicles derived from Escherichia coli. Proteomics 7 3143–3153.

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    Lee E.-Y. Choi D.-Y. Kim D.-K. Kim J.-W. Park J. O. Kim S. (2009 ). Gram-positive bacteria produce membrane vesicles: Proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles. Proteomics 9 5425–5436.

    Not in our library10.1002/pmic.200900338

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  123. 123.

    Levine A. Vannier F. Absalon C. Kuhn L. Jackson P. Scrivener E. (2006 ). Analysis of the dynamic Bacillus subtilis Ser/Thr/Tyr phosphoproteome implicated in a wide variety of cellular processes. Proteomics 6 2157–2173.

    Not in our library10.1002/pmic.200500352

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    Li X. Xing J. Li B. Wang P. Liu J. (2012 ). Use of tuf as a target for sequence-based identification of Gram-positive cocci of the genus Enterococcus, Streptococcus, coagulase-negative Staphylococcus, and Lactococcus. Ann. Clin. Microbiol. Antimicrob. 11:31.

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    Liew Y. K. Awang Hamat R. van Belkum A. Chong P. P. Neela V. (2015 ). Comparative exoproteomics and host inflammatory response in Staphylococcus aureus skin and soft tissue infections, bacteremia, and subclinical colonization. Clin. Vaccine Immunol. 22 593–603.

    Not in our library10.1128/cvi.00493-14

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    Lippmann C. Lindschau C. Vijgenboom E. Schroder W. Bosch L. Erdmann V. A. (1993 ). Prokaryotic elongation factor Tu is phosphorylated in vivo. J. Biol. Chem. 268 601–607.

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    Liu H. Cheng Z. Song W. Wu W. Zhou Z. (2014 ). Immunoproteomic to analysis the pathogenicity factors in leukopenia caused by Klebsiella pneumonia bacteremia. PLoS One 9:e110011.

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    Liu L. Wu R. Zhang J. Shang N. Li P. (2017 ). D-ribose interferes with quorum sensing to inhibit biofilm formation of Lactobacillus paraplantarum L-ZS9. Front. Microbiol. 8:1860.

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    López-Ochoa J. Montes-García J. F. Vázquez C. Sánchez-Alonso P. Pérez-Márquez V. M. Blackall P. J. (2017 ). Gallibacterium elongation factor-Tu possesses amyloid-like protein characteristics, participates in cell adhesion, and is present in biofilms. J. Microbiol. 55 745–752.

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    Lu F. Wang H. Wang S. Jiang W. Shan C. Li B. (2015 ). Enhancement of innate immune system in monocot rice by transferring the dicotyledonous elongation factor Tu receptor EFR. J. Integr. Plant Biol. 57 641–652.

    Not in our library10.1111/jipb.12306

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    Lylloff J. E. Hansen L. B. Jepsen M. Sanggaard K. W. Vester J. K. Enghild J. J. (2016 ). Genomic and exoproteomic analyses of cold- and alkaline-adapted bacteria reveal an abundance of secreted subtilisin-like proteases. Microb. Biotechnol. 9 245–256.

    Not in our library10.1111/1751-7915.12343

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    Maddi A. Haase E. Scannapieco F. (2014 ). Mass spectrometric analysis of whole secretome and amylase-precipitated secretome proteins from Streptococcus gordonii. J. Proteomics Bioinform. 7 287–295.

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  133. 133.

    Madeira J. P. Alpha-Bazin B. Armengaud J. Duport C. (2015 ). Time dynamics of the Bacillus cereus exoproteome are shaped by cellular oxidation. Front. Microbiol. 6:342.

    Not in our library10.3389/fmicb.2015.00342

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    Mantyh C. R. Gates T. S. Zimmerman R. P. Welton M. L. Passaro E. P. Vigna S. R. (1988 ). Receptor binding sites for substance P, but not substance K or neuromedin K, are expressed in high concentrations by arterioles, venules, and lymph nodules in surgical specimens obtained from patients with ulcerative colitis and Crohn disease. Proc. Natl. Acad. Sci. U.S.A. 85 3235–3239.

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    Massey R. C. Kantzanou M. N. Fowler T. Day N. P. Schofield K. Wann E. R. (2001 ). Fibronectin-binding protein A of Staphylococcus aureus has multiple, substituting, binding regions that mediate adherence to fibronectin and invasion of endothelial cells. Cell Microbiol. 3 839–851.

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  136. 136.

    McLean S. (2005 ). Do substance P and the NK1 receptor have a role in depression and anxiety? Curr. Pharm. Des. 11 1529–1547.

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    Mignard S. Flandrois J. P. (2007 ). Identification of Mycobacterium using the EF-Tu encoding (tuf) gene and the tmRNA encoding (ssrA) gene. J. Med. Microbiol. 56 1033–1041.

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    Mijouin L. Hillion M. Ramdani Y. Jaouen T. Duclairoir-Poc C. Follet-Gueye M. L. (2013 ). Effects of a skin neuropeptide (substance p) on cutaneous microflora. PLoS One 8:e78773.

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    Mikulik K. Zhulanova E. (1995 ). Sequencing of the tuf1 gene and the phosphorylation pattern of EF-Tu1 during development and differentiation in Streptomyces collinus producing kirromycin. Biochem. Biophys. Res. Commun. 213 454–461.

    Not in our library10.1006/bbrc.1995.2153

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    Min K.-W. Lee S.-H. Baek S. J. (2016 ). Moonlighting proteins in cancer. Cancer Lett. 370 108–116.

    Not in our library10.1016/j.canlet.2015.09.022

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    Mirzaei R. Saei A. Torkashvand F. Azarian B. Jalili A. Noorbakhsh F. (2016 ). Identification of proteins derived from Listeria monocytogenes inducing human dendritic cell maturation. Tumour Biol. 37 10893–10907.

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    Mishra S. Horswill A. R. (2017 ). Heparin mimics extracellular DNA in binding to cell surface-localized proteins and promoting Staphylococcus aureus biofilm formation. mSphere 2:e00135-17.

    Not in our library10.1128/msphere.00135-17

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    Mohan S. Hertweck C. Dudda A. Hammerschmidt S. Skerka C. Hallstrom T. (2014 ). Tuf of Streptococcus pneumoniae is a surface displayed human complement regulator binding protein. Mol. Immunol. 62 249–264.

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    Monahan I. M. Betts J. Banerjee D. K. Butcher P. D. (2001 ). Differential expression of mycobacterial proteins following phagocytosis by macrophages. Microbiology 147 459–471.

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    Montes-García J. F. Chincoya Martinez D. A. Vaca Pacheco S. Vázquez Cruz C. Sanchez Alonso P. Xicohtencatl Cortes J. (2018 ). Identification of two adhesins of Actinobacillus seminis. Small Rumin. Res. 167 100–103.

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    Nagai K. Domon H. Maekawa T. Hiyoshi T. Tamura H. Yonezawa D. (2019 ). Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection. Vaccine 37 160–168.

    Not in our library10.1016/j.vaccine.2018.11.015

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    Nascimento R. Gouran H. Chakraborty S. Gillespie H. W. Almeida-Souza H. O. Tu A. (2016 ). Corrigendum: the type II secreted Lipase/Esterase LesA is a key virulence factor required for Xylella fastidiosa pathogenesis in grapevines. Sci. Rep. 6:21575

    Not in our library10.1038/srep21575

  148. 148.

    N’Diaye A. Mijouin L. Hillion M. Diaz S. Konto-Ghiorghi Y. Percoco G. (2016 ). Effect of substance P in Staphylococcus aureus and Staphylococcus epidermidis virulence: implication for skin homeostasis. Front. Microbiol. 7:506.

    Not in our library10.3389/fmicb.2016.00506

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    N’Diaye A. R. Borrel V. Racine P.-J. Clamens T. Depayras S. Maillot O. (2019 ). Mechanism of action of the moonlighting protein EfTu as a substance P sensor in Bacillus cereus. Sci. Rep. 9:1304.

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  150. 150.

    Nega M. Dube L. Kull M. Ziebandt A. K. Ebner P. Albrecht D. (2015 ). Secretome analysis revealed adaptive and non-adaptive responses of the Staphylococcus carnosus femB mutant. Proteomics 15 1268–1279.

    Not in our library10.1002/pmic.201400343

  151. 151.

    Newcombe J. Mendum T. A. Ren C. P. McFadden J. (2014 ). Identification of the immunoproteome of the meningococcus by cell surface immunoprecipitation and MS. Microbiology 160 429–438.

    Not in our library10.1099/mic.0.071829-0

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    Nisole S. Krust B. Callebaut C. Guichard G. Muller S. Briand J. P. (1999 ). The anti-HIV pseudopeptide HB-19 forms a complex with the cell-surface-expressed nucleolin independent of heparan sulfate proteoglycans. J. Biol. Chem. 274 27875–27884.

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  153. 153.

    Nisole S. Said E. A. Mische C. Prevost M. C. Krust B. Bouvet P. (2002 ). The anti-HIV pentameric pseudopeptide HB-19 binds the C-terminal end of nucleolin and prevents anchorage of virus particles in the plasma membrane of target cells. J. Biol. Chem. 277 20877–20886.

    Not in our library10.1074/jbc.m110024200

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    O’Connor T. M. O’Connell J. O’Brien D. I. Goode T. Bredin C. P. Shanahan F. (2004 ). The role of substance P in inflammatory disease. J. Cell. Physiol. 201 167–180.

    Not in our library10.1002/jcp.20061

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    Olaya-Abril A. Prados-Rosales R. McConnell M. J. Martín-Peña R. González-Reyes J. A. Jiménez-Munguía I. (2014 ). Characterization of protective extracellular membrane-derived vesicles produced by Streptococcus pneumoniae. J. Proteomics 106 46–60.

    Not in our library10.1016/j.jprot.2014.04.023

  156. 156.

    Omer H. Alpha-Bazin B. Brunet J. L. Armengaud J. Duport C. (2015 ). Proteomics identifies Bacillus cereus EntD as a pivotal protein for the production of numerous virulence factors. Front. Microbiol. 6:1004.

    Not in our library10.3389/fmicb.2015.01004

  157. 157.

    Padilla-Reynaud R. Simao-Beaunoir A. M. Lerat S. Bernards M. A. Beaulieu C. (2015 ). Suberin regulates the production of cellulolytic enzymes in Streptomyces scabiei, the causal agent of potato common scab. Microbes Env. 30 245–253.

    Not in our library10.1264/jsme2.me15034

  158. 158.

    Peng Z. Vogel R. F. Ehrmann M. A. Xiong T. (2018 ). Identification and characterization of adhesion proteins in lactobacilli targeting actin as receptor. Mol. Cell. Probes 37 60–63.

    Not in our library10.1016/j.mcp.2017.08.002

  159. 159.
    Outer-Inner Membrane Vesicles Naturally Secreted by Gram-Negative Pathogenic Bacteria · 2015
    No notice
  160. 160.

    Petit F. M. Serres C. Auer J. (2014 ). Moonlighting proteins in sperm-egg interactions. Biochem. Soc. Trans. 42 1740–1743.

    Not in our library10.1042/bst20140218

  161. 161.

    Peton V. Bouchard D. S. Almeida S. Rault L. Falentin H. Jardin J. (2014 ). Fine-tuned characterization of Staphylococcus aureus Newbould 305, a strain associated with mild and chronic mastitis in bovines. Vet. Res. 45:106.

    Not in our library10.1186/s13567-014-0106-7

  162. 162.

    Pierson T. Matrakas D. Taylor Y. U. Manyam G. Morozov V. N. Zhou W. (2011 ). Proteomic characterization and functional analysis of outer membrane vesicles of Francisella novicida suggests possible role in virulence and use as a vaccine. J. Proteome Res. 10 954–967.

    Not in our library10.1021/pr1009756

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    Pinto P. M. Chemale G. de Castro L. A. Costa A. P. M. Kich J. D. Vainstein M. H. (2007 ). Proteomic survey of the pathogenic Mycoplasma hyopneumoniae strain 7448 and identification of novel post-translationally modified and antigenic proteins. Vet. Microbiol. 121 83–93.

    Not in our library10.1016/j.vetmic.2006.11.018

  164. 164.

    Plikat U. Voshol H. Dangendorf Y. Wiedmann B. Devay P. Muller D. (2007 ). From proteomics to systems biology of bacterial pathogens: approaches, tools, and applications. Proteomics 7 992–1003.

    Not in our library10.1002/pmic.200600925

  165. 165.

    Polekhina G. Thirup S. Kjeldgaard M. Nissen P. Lippmann C. Nyborg J. (1996 ). Helix unwinding in the effector region of elongation factor EF-Tu-GDP. Structure 4 1141–1151.

    Not in our library10.1016/s0969-2126(96)00122-0

  166. 166.

    Pouttu R. Puustinen T. Virkola R. Hacker J. Klemm P. Korhonen T. K. (1999 ). Amino acid residue Ala-62 in the FimH fimbrial adhesin is critical for the adhesiveness of meningitis-associated Escherichia coli to collagens. Mol. Microbiol. 31 1747–1757.

    Not in our library10.1046/j.1365-2958.1999.01311.x

  167. 167.

    Prados-Rosales R. Baena A. Martinez L. R. Luque-Garcia J. Kalscheuer R. Veeraraghavan U. (2011 ). Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J. Clin. Invest. 121 1471–1483.

    Not in our library10.1172/jci44261

  168. 168.

    Premkumar L. Kurth F. Duprez W. Groftehauge M. K. King G. J. Halili M. A. (2014 ). Structure of the Acinetobacter baumannii dithiol oxidase DsbA bound to elongation factor EF-Tu reveals a novel protein interaction site. J. Biol. Chem. 289 19869–19880.

    Not in our library10.1074/jbc.m114.571737

  169. 169.

    Prezioso S. M. Brown N. E. Goldberg J. B. (2017 ). Elfamycins: inhibitors of elongation factor-Tu. Mol. Microbiol. 106 22–34.

    Not in our library10.1111/mmi.13750

  170. 170.

    Pribyl T. Moche M. Dreisbach A. Bijlsma J. J. Saleh M. Abdullah M. R. (2014 ). Influence of impaired lipoprotein biogenesis on surface and exoproteome of Streptococcus pneumoniae. J. Proteome Res. 13 650–667.

    Not in our library10.1021/pr400768v

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    Pukatzki S. Ma A. T. Sturtevant D. Krastins B. Sarracino D. Nelson W. C. (2006 ). Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system. Proc. Natl. Acad. Sci. U.S.A. 103 1528–1533.

    Not in our library10.1073/pnas.0510322103

  172. 172.

    Ramiah K. van Reenen C. A. Dicks L. M. T. (2008 ). Surface-bound proteins of Lactobacillus plantarum 423 that contribute to adhesion of Caco-2 cells and their role in competitive exclusion and displacement of Clostridium sporogenes and Enterococcus faecalis. Res. Microbiol. 159 470–475.

    Not in our library10.1016/j.resmic.2008.06.002

  173. 173.

    Raymond B. B. A. Djordjevic S. (2015 ). Exploitation of plasmin(ogen) by bacterial pathogens of veterinary significance. Vet. Microbiol. 178 1–13.

    Not in our library10.1016/j.vetmic.2015.04.008

  174. 174.

    Raymond B. B. A. Jenkins C. Seymour L. M. Tacchi J. L. Widjaja M. Jarocki V. M. (2015 ). Proteolytic processing of the cilium adhesin MHJ_0194 (P123J) in Mycoplasma hyopneumoniae generates a functionally diverse array of cleavage fragments that bind multiple host molecules. Cell. Microbiol. 17 425–444.

    Not in our library10.1111/cmi.12377

  175. 175.

    Raymond B. B. A. Tacchi J. L. Jarocki V. M. Minion F. C. Padula M. P. Djordjevic S. P. (2013 ). P159 from Mycoplasma hyopneumoniae binds porcine cilia and heparin and is cleaved in a manner akin to ectodomain shedding. J. Proteome Res. 12 5891–5903.

    Not in our library10.1021/pr400903s

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    Raymond B. B. A. Turnbull L. Jenkins C. Madhkoor R. Schleicher I. Uphoff C. C. (2018 ). Mycoplasma hyopneumoniae resides intracellularly within porcine epithelial cells. Sci. Rep. 8:17697.

    Not in our library10.1038/s41598-018-36054-3

  177. 177.
    Quantitative proteomics unravels that the post-transcriptional regulator Crc modulates the generation of vesicles and secreted virulence determinants of Pseudomonas aeruginosa · 2015
    Not checked
  178. 178.
    A Two-Component Regulatory System Impacts Extracellular Membrane-Derived Vesicle Production in Group A Streptococcus · 2016
    No notice
  179. 179.

    Robinson M. W. Buchtmann K. A. Jenkins C. Tacchi J. L. Raymond B. B. A. To J. (2013 ). MHJ_0125 is an M42 glutamyl aminopeptidase that moonlights as a multifunctional adhesin on the surface of Mycoplasma hyopneumoniae. Open Biol. 3:130017.

    Not in our library10.1098/rsob.130017

  180. 180.

    Rubiano-Labrador C. Bland C. Miotello G. Armengaud J. Baena S. (2015 ). Salt stress induced changes in the exoproteome of the halotolerant bacterium tistlia consotensis deciphered by proteogenomics. PLoS One 10:e0135065.

    Not in our library10.1371/journal.pone.0135065

  181. 181.

    Ruyechan W. T. Olson J. W. (1992 ). Surface lysine and tyrosine residues are required for interaction of the major herpes simplex virus type 1 DNA-binding protein with single-stranded DNA. J. Virol. 66 6273–6279.

    Not in our library10.1128/jvi.66.11.6273-6279.1992

  182. 182.

    Rychli K. Grunert T. Ciolacu L. Zaiser A. Razzazi-Fazeli E. Schmitz-Esser S. (2016 ). Exoproteome analysis reveals higher abundance of proteins linked to alkaline stress in persistent Listeria monocytogenes strains. Int. J. Food Microbiol. 218 17–26.

    Not in our library10.1016/j.ijfoodmicro.2015.11.002

  183. 183.

    Saad N. Urdaci M. Vignoles C. Chaignepain S. Tallon R. Schmitter J. M. (2009 ). Lactobacillus plantarum 299v surface-bound GAPDH: a new insight into enzyme cell walls location. J. Microbiol. Biotechnol. 19 1635–1643.

    Not in our library10.4014/jmb.0902.0102

  184. 184.

    Sajid A. Arora G. Gupta M. Singhal A. Chakraborty K. Nandicoori V. K. (2011 ). Interaction of Mycobacterium tuberculosis elongation factor Tu with GTP Is regulated by phosphorylation? J. Bacteriol. 193 5347–5358.

    Not in our library10.1128/jb.05469-11

  185. 185.

    Sanchez B. Bressollier P. Urdaci M. C. (2008 ). Exported proteins in probiotic bacteria: adhesion to intestinal surfaces, host immunomodulation and molecular cross-talking with the host. FEMS Immunol. Med. Microbiol. 54 1–17.

    Not in our library10.1111/j.1574-695x.2008.00454.x

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    Sanchez-Campillo M. Bini L. Comanducci M. Raggiaschi R. Marzocchi B. Pallini V. (1999 ). Identification of immunoreactive proteins of Chlamydia trachomatis by Western blot analysis of a two-dimensional electrophoresis map with patient sera. Electrophoresis 20 2269–2279.

    Not in our library10.1002/(sici)1522-2683(19990801)20:11<2269::aid-elps2269>3.0.co;2-d

  187. 187.

    Sanderson-Smith M. L. De Oliveira D. M. P. Ranson M. McArthur J. D. (2012 ). Bacterial plasminogen receptors: mediators of a multifaceted relationship. J. Biomed. Biotechnol. 2012:272148.

    Not in our library10.1155/2012/272148

  188. 188.

    Sandig H. McDonald J. Gilmour J. Arno M. Lee T. H. Cousins D. J. (2009 ). Fibronectin is a TH1-specific molecule in human subjects. J. Allergy Clin. Immunol. 124 528.e5–535.e5.

    Not in our library10.1016/j.jaci.2009.04.036

  189. 189.

    Sasikumar A. N. Perez W. B. Kinzy T. G. (2012 ). The many roles of the eukaryotic elongation factor 1 complex. Wiley Interdiscip. Rev. RNA 3 543–555.

    Not in our library10.1002/wrna.1118

  190. 190.

    Schaumburg J. Diekmann O. Hagendorff P. Bergmann S. Rohde M. Hammerschmidt S. (2004 ). The cell wall subproteome of Listeria monocytogenes. Proteomics 4 2991–3006.

    Not in our library10.1002/pmic.200400928

  191. 191.

    Scherl A. Francois P. Bento M. Deshusses J. M. Charbonnier Y. Converset V. (2005 ). Correlation of proteomic and transcriptomic profiles of Staphylococcus aureus during the post-exponential phase of growth. J. Microbiol. Methods 60 247–257.

    Not in our library10.1016/j.mimet.2004.09.017

  192. 192.

    Schoonbeek H.-J. Wang H.-H. Stefanato F. L. Craze M. Bowden S. Wallington E. (2015 ). Arabidopsis EF-Tu receptor enhances bacterial disease resistance in transgenic wheat. New Phytol. 206 606–613.

    Not in our library10.1111/nph.13356

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