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Role of Heat Shock Proteins (HSP70 and HSP90) in Viral Infection

Anna Lubkowska, Waldemar Pluta, Aleksandra Strońska and 1 more

International Journal of Molecular Sciences · 2021 · Review · CC BY

doi:10.3390/ijms22179366

Abstract

Heat shock proteins (HSPs) are a large group of chaperones found in most eukaryotes and bacteria. They are responsible for the correct protein folding, protection of the cell against stressors, presenting immune and inflammatory cytokines; furthermore, they are important factors in regulating cell differentiation, survival and death. Although the biological function of HSPs is to maintain cell homeostasis, some of them can be used by viruses both to fold their proteins and increase the chances of survival in unfavorable host conditions. Folding viral proteins as well as replicating many different viruses are carried out by, among others, proteins from the HSP70 and HSP90 families. In some cases, the HSP70 family proteins directly interact with viral polymerase to enhance viral replication or they can facilitate the formation of a viral replication complex and/or maintain the stability of complex proteins. It is known that HSP90 is important for the expression of viral genes at both the transcriptional and the translational levels. Both of these HSPs can form a complex with HSP90 and, consequently, facilitate the entry of the virus into the cell. Current studies have shown the biological significance of HSPs in the course of infection SARS-CoV-2. A comprehensive understanding of chaperone use during viral infection will provide new insight into viral replication mechanisms and therapeutic potential. The aim of this study is to describe the molecular basis of HSP70 and HSP90 participation in some viral infections and the potential use of these proteins in antiviral therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The discovery of Heat Shock Proteins (HSPs) is attributed to the Italian geneticist Ferruccio Ritossa, who during his research mistakenly increased the incubation temperature of Drosophila melanogaster larvae, which resulted in an increased transcription of genes of proteins unknown at that time. Less than 10 years later it was noticed that the proteins discovered by Ritossa prevented damage to cells which were associated with abnormal proteins resulting from heat shock. Later studies have shown that HSP can be induced not only by temperature but also by other stressors, including starvation, hypoxia, physiological or environmental attacks, chemical or UV exposure and the invasion of pathogens.

The division of HSP proteins is based on their molecular weight: there are small HSPs (sHSP), i.e., HSP21 and HSP10, medium HSPs, i.e., HSP60 and HSP70, and large HSPs, i.e., HSP90 and HSP100. Chaperones of larger molecular sizes than 60 kDa are ATP-dependent and utilize their enzymatic activity to induce conformational changes in the client polypeptide by hydrolyzing adenosine triphosphate (ATP) to adenosine diphosphate (ADP). In terms of expression, two types of HSP are distinguished: stress-induced isomers, the expression level of which depends on the presence of a stressor and native forms with constant, stress-independent expression. HSPs are located in various cell structures, including the nucleus, mitochondria, chloroplasts, endoplasmic reticulum and cytosol in all types of prokaryotes and eukaryotes. They are expressed during the cell cycle, embryogenesis and differentiation, and are stimulated by growth factors.

Their main role is to protect cells against stressors by participating in the correct folding of newly formed proteins, repairing misfolded proteins and by participating in the transport of proteins to their site of action. HSPs usually make up about 5–10% of the total protein in most cells but their intracellular concentration may increase within a few minutes under the influence of stressors up to 20 times in order to suppress or attenuate undesired effects.

In physiological conditions and in the absence of stressors, HSPs are associated with heat shock factors (HSF), especially HSF-1. An increase in the number of damaged proteins causes the detachment of HSP from HSF in order to bind the damaged protein. Consequently, there is an increase in the number of free HSFs in the cell, which function as transcription factors and bind to heat shock DNA elements, triggering the expression of HSP, a so-called heat shock response HSR. This increase in HSP expression means that free HSF is rebound, reducing HSP gene transcription and inhibiting HSF binding to DNA. This approach enables HSPs to independently regulate their own expression. During cellular stress, the level of HSP in the cytoplasm increases and their transport takes place mainly to the cell nucleus, where they protect DNA, pre-mRNA, pre-ribosomal and nuclear proteins against damage and degradation. They also participate in the activation of specific genes.

Although HSPs are protective proteins, they can be turned against the organism in which they are found. Viruses lacking their HSPs use the host’s HSP to fold their proteins and increase the effectiveness of infection. A better understanding of the mechanisms of viral infections in which HSPs participate would allow for the development of more effective antiviral drugs based on these proteins. HSP70 and HSP90 inhibitors show great therapeutic potential. The aim of this review is to present the latest reports on the role of HSP70 and HSP90 in viral infections and to present these proteins as an effective therapeutic target.

2.1. HSP70

As one of the most ubiquitous molecular chaperones located in all the cellular compartments of eukaryotes, HSP70s regulate every aspect of cellular proteostasis, including: the folding of both nascent and misfolded proteins; protein assembly and the regulation of their activity; the translocation into mitochondria, chloroplasts and the endoplasmic reticulum; the degradation of and prevention from dismantling protein aggregates. HSP70 is composed of two large, functional domains: the N-terminal nucleotide-binding domain (NBD) and the C-terminal substrate-binding domain (SBD). The NBD is about 44 kDa and provides energy to power HSP70 activity by binding and hydrolyzing ATP to ADP. It is divided into two lobes (I and II), which are further divided into two subdomain regions (IA, IB and IIA, IIB). The characteristic structure of subdomains forms a V-shaped cleft where the nucleotide binds. In turn, SBD (25 kDa) is a tweezers-like binding site for polypeptide substrates and is divided into two domains called α and β. A 12-kDa β-SBD is organized such as a sandwich and is made up of two antiparallel β-sheets of four strands each. The β-domain contains the substrate-binding site used for binding misfolded proteins which is located between the two β sheets. The substrate-binding pocket is highly hydrophobic and displays a high affinity for hydrophobic substituents such as Leu. α-SBD is a 15-kDa α-helical subdomain which forms a lid that covers the substrate-binding cleft and stabilizes the loop regions of the β-subdomain. The domains are connected by the interdomain linker, which is composed of 10–12 highly conserved hydrophobic amino acids which assume an unstructured conformation in the ADP-bound state and a β-stranded conformation in the ATP-bound state. SBD is similar in shape to tweezers, allowing HSP70 to interact with polypeptides and protein complexes regardless of their size. Moreover, this domain can stabilize these units by interacting with folding intermediators and folded pieces of proteins. Interaction with folded proteins is not constant and is regulated by an allosteric mechanism. It involves the hydrolysis of ATP and the rebinding of ATP in NBD with the binding and release of substrate polypeptides. The allosteric mechanism of HSP70 can be modified by J domain proteins (JDP) and nucleotide exchange factors (NEF).

Such a wide spectrum of activity of HSP70s proves that these proteins, in order to adapt to the conditions of growth and stress in the cell, are able to act on a variety of substrates. There are at least 14 proteins within the human HSP70 family, which differ in terms of expression level, amino acid composition and subcellular localization. Proteins can be stress induced (e.g., HSPA1 and HSP6) or constitutively expressed (e.g., HSPA5, HSPA8 and HSPA9). The chaperone activity of a protein consists of the hydrolysis of ATP. The interaction with unfolded protein begins with the binding of HSP70 to its substrates. The initially low affinity increases significantly after ATP is hydrolyzed to ADP by the cochaperone HSP40. Finally, with the help of nucleotide exchange factors, ADP dissociates to reset the cycle. The most important functions of the HSP70 isoforms are presented in Table 1.

2.2. HSP90

A characteristic feature of all HSP90 family proteins is the identical domain structure. It consists of the N-terminal domain (NTD), the middle domain (M domain) and the carboxy-terminal domain (CTD). NTD contains in its structure an ATP binding site that is essential for the ATPase activity of HSP90. It is required for the chaperone cycle and protein binding of the HSP90 client. The MD domain has a characteristic way of controlling the functions of HSP90 through the binding of phosphate to the ATP specified for NTD. Thus, the MD domain influences the ATPase activity of HSP90. There are two key sites in the CTD domain: one for calmodulin binding, and the other for HSP9 homodimerization. In addition, there is a nucleotide binding site that opens after taking the N-terminal site and serves as an allosteric regulator of N-terminal ATPase activity.

During the ATPase cycle, HSP90 undergoes various transformations of conformational states. The first intermediate state is the binding of ATP to NTD, which leads to the closure of the ATP cover over the bound nucleotide. The subsequent conformation changes lead to the dimerized state at the amino terminus (closed state 1) with replaced segments in NTD and compacting the distance between MD and NTD (closed state 2), as a result of which ATPase has a competent conformation. The HSP90 chaperone cycle ends with the release of ADP and phosphate and the dissociation of the amino terminus.

Heat shock factor 1 (HSF1) is mainly responsible for the expression of HSP90 at the transcription stage. Its functioning is based on the regulation of the heat shock response (HSR) in eukaryotic cells. HSF1 is also the major regulator of HSP90 levels in cells. This large influence of HSF1 on HSP90 resulted in the development of a complex series of regulatory mechanisms, including transcription, HSF1 trimerizations, cooperative binding to HSE, post-translational modifications and the ability of HSF1 to directly detect stress. All these mechanisms integrate different signals, resulting in a change in HSP90 concentration in cells.

The functions of HSP90 are modulated by numerous post-translational modifications. These include acetylation, phosphorylation, sumoylation and S-nitrosylation. Certain changes in the acetylation state are key regulators of co-chaperone binding, including HSP90 hyperacetylation, causing the inability to bind to co-chaperone p23, loss of guardian activity and impaired activation of the glucocorticoid receptor (GR). Phosphorylation has been shown to slow down the conformational cycle of HSP90 and to influence client maturation and interactions with the co-chaperone. Protein phosphatase PP5 is the co-chaperone of HSP90 that affects the phosphorylation status. In the absence of PP5, a state of hyperphosphorylation occurs, which negatively affects the maturation of the client. S-nitrosylation of HSP90 in CTD inhibits the ATPase reaction and reduces the activating effect of HSP90 on client endothelial nitric oxide synthase (eNOS). It can be concluded that there is an eNOS feedback mechanism. S-nitrosylation affects the ATPase activity of HSP90 as well as its chaperone activity. The most important functions of the HSP90 isoforms are presented in Table 2.

The determinants of HSP90 customers are still the subject of many researches and discussions. It is still not entirely clear how HSP90 recruits its customers, but it is known that they are not aware of any common binding patterns (e.g., hydrophobic sequences).

3.1. RNA Viruses

Table 3 shows stages of infection of RNA viruses, which use the HSP70 and/or HSP90 host. The following subsection focuses on viruses in which both HSP70 and HSP90 are involved.

3.1.1. Human Enterovirus (EV-71)

Human enterovirus 71 (EV-71) is a virus of the Enterovirus genus in the Picornaviridae family. EV-71 has a positive sense single-stranded RNA genome. It is approximately 7400 bp in length. Most often it causes large outbreaks of hand-foot-and-mouth disease (HFMD), as well as aseptic meningitis and encephalitis. EV-71 is stated to be responsible for the epidemics of severe neurological diseases in Asia, Europe and the USA.

In the research of Xu et al. it is shown that HSP70 present on the surface of host cells can act as a site of attachment for EV-71. This allows for the initial binding of EV-71 to the host cells and subsequent infection, though the amount of viral cells attached to the host cell surface may not only determine the effectiveness of the infection. These studies also provided information that HSP70 established an additional route for EV-71 entry into host cells. The chaperone knockdown with lipofectamine 2000 did not eliminate the infection. This may indicate that the interaction of the chaperone protein with EV-71 enables the promotion of the attachment of the virus to other viral binding cell receptors, and then enhances viral endocytosis in the host cells.

More detailed studies on the contribution of proteins from the HSP70 family were carried out by Yu-Siang et al.. The study analyzed the role of HSPA1, HSPA8 and HSPA9 at each stage of the EV-71 replication cycle. The results proved that the studied proteins are involved in all phases of the virus life cycle. Deficiency in any of the proteins in the HSP70 subnetwork leads to a significant reduction in viral internalization. The entry of EV-71 into the cells takes place through endocytosis via the scavenger receptor class B member 2 (SCARB2), which depends on clathrin and dynamin 2. HSPA8 has the ability to separate the clathrin triskelion from vesicles covered with clathrin; thus, influencing the internation of the virus. The current knowledge regarding the effects of HSPA1 and HSPA9 in promoting the entry of EV-71 into host cells is limited.

Yueh-Liang Tsou et al. showed the direct interaction of HSP90 with EV-71 on the cell surface. The use of HSP90 inhibitors such as geldanamycin (GA), siRNA or antibodies, disrupted the entry of the virus at an early stage. In addition, viral replication was disrupted and the stability of the capsid proteins was impaired at the post-translational level. Following treatment with inhibitors, the newly synthesized capsid proteins lost the ability to assemble properly in the infected cell.

3.1.2. Dengue Virus (DENV)

Dengue virus (DENV) is a virus from the Flaviviridae family of the Flavivirus genus. DENV is an enveloped, single-stranded, positive RNA virus of approximately 11 kb. The virus is transmitted by female Aedes aegypti mosquitoes and causes hemorrhagic fever. The spectrum of clinical disease can vary from asymptomatic to a wide range of syndromes with severe clinical symptoms.

Jorge Reyes-del Valle et al. suggested that HSP90 and HSP70 are involved in DENV entry into host cells. They proved this by using antibodies against HSP90 and HSP70 in an infection inhibition assay. The results show that anti-HSP90 and anti-HSP70 antibodies block DENV infectivity in neuroblastoma cells. Additionally, both HSP90 and HSP70 associate with membrane lipid rafts in response to DENV infection.

Several studies have shown that HSP70 acts as permeable DENV receptor in mammalian and mosquito cells. HSPA5 (or otherwise called GRP78), a member of the HSP70 family, was identified as the DENV receptor in the HepG2 cell line by a viral overlay protein (VOPBA) binding assay coupled with mass spectrometry. The use of a specific antibody directed against the N-terminal domain of GRP78 leads to the blockage of this protein on the cell surface, resulting in a reduction in DENV production. On the other hand, the use of an inhibitor that binds to the C-terminal domain results in a higher viral production depending on the dose used.

Heat shock stress has been shown to enhance replication in the U937 cell line by increasing the expression of HSP70 and HSP90 on the cell surface, especially in lipid rafter microdomains. Interestingly, the increase in HSP70 and HSP90 expression induced by heat stress did not result in increased DENV binding, but facilitated viral entry. The findings suggest that HSP70 and HSP90 are necessary for DENV entry into the cell, and that heat shock stress is optimal for cell replication in the U937 cell line.

Research by Taguwa et al. reports that HSP70 is essential for the life cycle of DENV, including virus entry, virus replication and virion production. In order to confirm the role of HSP70 in virus entry into the cell, they used a specific HSP70 inhibitor—JG40. Treatment of cells with this inhibitor reduced viral RNA.

Studies by Howe et al. report that the amount of inducible HSP70 increases during DENV infection and is used by the virus during its entry into the host cell. Interestingly, the use of an HS-10 inhibitor specific for HSP90 also increases the level of inducible HSP70 on the surface of infected cells, which in turn results in increased infectivity in the U937 + DC-SIGN cell line. It is shown that the use of an HS-72 inhibitor specific for inducible HSP70 before infection reduces the infectivity of DENV.

3.1.3. Influenza A Virus (IAV)

The influenza A virus (IAV) genome consists of eight segmented, negative RNAs. Viral RNA (vRNA) together with viral RNA-dependent RNA polymerase subunits—PB1, PB2 and PA—and NP nucleoprotein form viral ribonucleoprotein (vRNP) complexes.

HSP90 stabilizes viral polymerase activity by binding to its PB2 subunit. HSP90 is transported to the cell nucleus with PB2 or the PB1–PB2 complex. The HSP90–PB2 complex interacts with PB1–PA in the cell nucleus where a ternary complex is formed and HSP90 is released from PB2. The accumulation of HSP90 in the nucleus through interaction with viral polymerases is needed for the regulation of RNA virus synthesis in the nucleus.

In addition to the role of HSP90 in the stabilization of viral polymerase and in nuclear transport, HSP90 promotes influenza A-mediated apoptosis. It activates the caspase cascade, essential for viral replication, pathogenesis and virulence. HSP90 has also been shown to counteract the degradation of influenza A (NA) neuraminidase and increase its stability. The formation of the HSP90-NA complex increases the viability of the cells, which leads to more virus production.

Studies have shown that HSP70 can inhibit IAV replication by disrupting viral polymerase binding to viral RNA or by preventing the RNP complex from being exported to the nucleus.

In addition, studies by Manzoor et al. proved that HSP70 interacts and translocates into the nucleus with PB2 monomers or PB2/PB1 heterodimers, which, consequently, may aid viral polymerase complex formation. They also confirmed that the precipitation of HSP70 using HSP70-specific siRNA reduced both IAV transcription and replication. The performed immunoprecipitation showed that HSP70 is co-precipitated with the PB2/PB1 heterodimer, thanks to the incorporation of the PA subunit into the PB1/PA or PB2/PB1/PA heterodimer.

3.1.4. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

The outbreak of the SARS-CoV-2 pandemic in 2019 drew the attention of scientists from around the world to focus on researching and trying to combat it. SARS-CoV-2 belongs to the Coronavirinae subfamily of the Coronaviridae family. It is a single-stranded, positive RNA virus. Recent sequencing has shown it to be around 29.9 kb in length. SARS-CoV-2 is composed of four structural proteins—S, E, M and N—and sixteen non-structural proteins—NSP1-16. SARS-CoV-2 causes a disease commonly known as the 2019 coronavirus disease (COVID-19). Many COVID-19 patients develop acute respiratory distress syndrome (ARDS). According to Wu et al. the development of ARDS is responsible for the prognosis in patients, which is exacerbated by the excessive permeability of the endothelium in the lung tissues. Recent studies, however, report that HSP90 inhibitors inhibit endothelial damage and restore endothelial barrier functions. Studies in mice proved that HSP90 inhibitors such as 17-AAG and Luminespib induced a response to unfolded proteins, thereby protecting endothelial cells of the pulmonary aorta and microvessels of the lungs.

The S glycoprotein plays an important role during SARS-CoV-2 entry into host cells via the ACE2 receptor, which is located in the host cell membrane. The entry of the virus into the cell takes place by endocytosis or fusion with the surface membrane. The spike of the viral protein binds to ACE2. For the virus to enter the cell, the ACE2-binding spine must be split (activated) by a serine protease similar to 3C-3CLpro for the spike fusion domains to function. The fusion ends with the transfer of the genomic and protein content of the SARS-CoV-2 virus to the cytosol; thus, starting the replication cycle.

Alreshidi et al. hypothesized that aspirin-induced HSP70 and HSP90 bind to S-ACE2 and/or AngI, making ACE2 unavailable or at least less accessible to SARS-CoV-2, thereby inhibiting cytokine storms and ARDS. In addition, the research included simulating the docking of selected drugs. Of the more than 10 substances, only piperaquine and aspirin interacted quite efficiently with HSP70/90-AngII compared to HSP70/90-S-ACE2, forming a relatively stable complex. It is worth noting, however, that this experiment was carried out in silico and, therefore, requires validation in in vitro/in vivo tests. Wyler et al. investigated the effect of HSP90 on the replication of SARS-CoV-2 in the Calu-3 cell line, using the inhibitors of HSP90—Onalespib, Ganetespib and 17-(allylamino)-17-demethoxygeldanamycin (17-AAG). Reduced virus yield (about 50–70%) was obtained while maintaining cell viability. RNA sequencing was performed in healthy and infected cells to verify whether the use of HSP90 inhibitors reduced the amount of virus. The results show that in the infected cells, the intracellular RNA of the virus was reduced comparably to the amount of the virus. HSP90 inhibition reduced viral replication and the inflammatory response, particularly of pro-inflammatory cytokines such as IL-6, CXCL10 and CXCL11. The team of Li et al. was also interested in the 17-AAG inhibitor. In their experiment, they proved that 17-AAG strongly inhibits both SARS-CoV and SARS-CoV-2 replication. Another inhibitor of HSP-90 is geldanamycin, the effectiveness of which was confirmed by the team of Sultan et al.. The performed computational analysis of data from RNA sequencing of patients confirmed the inhibition of SARS-CoV-2 growth.

In studies by Joel Selkrig et al. attempts were made to disturb the SARS-CoV-2-induced destabilization of HSP90 by the use of tanespimycin—an HSP90 inhibitor. The resulting inhibition of viral proliferation provided convincing evidence that SARS-CoV-2 requires the presence of HSP90 for proliferation during infection.

3.2. DNA Viruses

Table 4 shows collected DNA viruses, which at different stages of infection use the HSP70 and/or HSP90 host. The following subsection focuses on viruses in which both HSP70 and HSP90 are involved.

3.2.1. Human Hepatitis B Virus (HBV)

Human hepatitis B virus (HBV) belongs to the Hepadnaviridae family and can cause acute and chronic liver disease. The core protein (HBc) plays an essential role in the viral life cycle, which is organized into two domains: the C-terminal domain that regulates viral replication and the N-terminal domain that is involved in the core assembly.

In domain C, there is the Cp149 protein which is known to be able to spontaneously form a capsid under appropriate in vitro and in vivo conditions. The capsid is an important structure that protects the viral DNA from external influences. There are few reports of the function of heat shock proteins in capsid formation. Shim et al.’s research proves that for HSP90 to facilitate viral capsid assembly, it must first be activated by p23 and ATP, with which it will form a complex that facilitates the maturation of the client protein. Activated HSP90 facilitates the assembly of the HBV capsid during encapsidation.

In their research, Wook Seo et al. proved that HSP70 synergistically increases the formation of HBV capsid with HSP90. They also theorized that the increased folding resulted from catalyzing the formation of the hexamer core protein. Nevertheless, there is still no confirmation of this theory in the literature. The results on the influence of HSP on HBV capsid formation may lead to the development of new therapeutic strategies for the treatment of HBV infection and the development of hepatocellular carcinoma (HCC) in the future.

3.2.2. Herpes Simplex Virus-1 (HSV-1)

Herpes Simplex Virus-1 (HSV-1) is a DNA-virus which belongs to the herpesviridae family. The virus genome is about 152 kb in size, whereas the virion diameter ranges from 150 to 300 nm. It is one of the most common and contagious viruses that produce viral infections in most humans. The virus can be transmitted by contact with a person going through an infection reactivation and shedding the virus, most often when the reactivation in a person is asymptomatic.

HSP90 is crucial for gene expression on many levels such as transcription and translation, among others. It regulates the location of the virus DNA polymerases through relocating them from the cell nucleus into the cytoplasm, where the polymerase is later degraded in the ubiquitin-proteasome pathway when the HSP90 function was inhibited.

HSP90 is involved in HSV-1 infection. It plays an important role in the early stages, especially when entering the nucleus as well as during the replication. HSV-1 uses the HSP90 chaperone during infection whereas the viral polymerase may be a client of HSP90. HSP90β participates in the formation of the BALF5 and BMRF1 catalytic subunits complex of the viral polymerase during its transport. HSP90 is also able to inhibit the intracellular nuclear transport of the HSV-1 capsid protein by co-localizing with acetylated tubulin and the capsid protein VP5, where HSP90 inhibitors disrupt its binding to the acetylated tubulin.

The HSV-1 virus may be reduced in amount by the AT-522 inhibitor at the exit of the viral nucleocapsid from the nucleus as well as during the expression and translocation of nuclear proteins such as pUL31 and pUL34.

In an HSV-1-infected cell nucleus near the viral replication compartments, virus-induced chaperone-enriched (VICE) foci are formed, which are the locus of a higher concentration of HSP70/HSP40. The HSP90 chaperone system engages HSP70/HSP40 in eukaryotes. HSP90 is found within viral replication compartments as well as in the adjacent to VICE foci. HSP70 and Hsc70/HSP40 are redistributed to those sites. These are also located by the HSV-1 viral portal protein which is a structural component of the viral capsids. The virus possibly creates a mechanism to sequester modified proteins in order to prevent triggering an antiviral response.

HSP90 promotes the translation of the conserved herpesvirus protein kinase (CHPK) of HSV-1 as well as of other viruses. CHPK plays a major role in gene expression, virus DNA replication, exiting the capsid nucleus and repair of the damaged DNA. In an infected cell, the HSP subpopulation is in a state of increased activation, similar to what occurs in neoplasm cells. Such a state suggests that HSP90 activation can be a common cell reaction to various stress factors.

HSP70 translocation from the cytosol to the nucleus is activated by the immediate-early viral protein, ICP0, a regulator of viral gene expression. Hsc70, components of the 26S proteasome and virus UL6 portal protein are co-localized, altogether creating a channel for DNA entry and exit from the capsid. UL6 is highly ubiquitinated in the nucleus, indicating that Hsc70 may be responsible for the correct folding and degradation of UL6 in the ubiquitin–proteasome pathway.

3.2.3. The Hepatitis C Virus (HCV)

HCV causes hepatitis C, the frequency of which is difficult to estimate due to the long latency period. Structurally, HCV is a small, enveloped virus of the Flaviviridae family. Its positive RNA encodes a polyprotein that is cut by viral and cellular proteases to produce structural and nonstructural proteins.

Research by Khachatoorian et al. confirmed the role of HSP70 in HCV replication. They explained this through a knockdown of HSP70 which led to a reduction in virus production. HBD-mediated action of the NS5A/HSP70 complex is involved in the NS5A-dependent translation of the HCV genome via IRES. Gonzalez et al. as well as Lim et al. showed that HSP70 knockdown reduces IRES-mediated translation and protein production. The NS5A/HSP70 interaction is critical for viral proliferation. A study has also been carried out which shows that the related heat shock protein Hsc70 also binds directly to NS5A; however, HSC70 has a different function than HSP70, and is involved in the formation of an infectious virion.

As with many other viruses, HSP90 enhances HCV replication by contributing to the regulation of viral polymerase activity. HSP90 stabilizes both the phosphoinositide kinase 1 (PDK1)-dependent kinase and the kinase preceding the NS5 PRK2 phosphorylation kinase, which indirectly affects the activity of NS5 polymerase. HSP90 also influences the maturation of HCV protein kinase 2/3 (NS2/3). After translation, this kinase is cleaved into two separate proteins, which is crucial for the maturation of the NS2/3 protein, and HSP90 is responsible for the correct folding of the newly formed NS2/3 protein. In addition, HSP90, with the help of the FKBP8 gene (folding and transport gene), forms a complex with NS5 and regulates its activity. The inhibition of the HSP90–NS5A complex formation leads to the inhibition of viral replication.

4. Conclusions

Members of the HSP70 and HSP90 families are involved in viral infections in many different ways. First, they support viruses when entering host cells by forming complexes on the cell surface. They also support viruses during their replication by directly interacting with the viral polymerase. HSP70 and HSP90 are important for viral gene expression. They are involved in assembling the capsid of some viruses. Viruses use the HSP70 and HSP90 proteins to fold their proteins and increase their chances of survival under unfavorable host conditions. A comprehensive knowledge of the use of chaperones during viral infection would provide new insight into viral replication mechanisms and potential therapies. The use of newer and more effective inhibitors directed against HSP70 and HSP90 proves that they are a very good therapeutic target in viral infections.

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    Mosser D.D., Caron A.W., Bourget L., Meriin A.B., Sherman M.Y., Morimoto R.I., Massie B. The Chaperone Function of hsp70 Is Required for Protection against Stress-Induced Apoptosis. Mol. Cell. Biol. 2000;20:7146-7159.

    Not in our library10.1128/mcb.20.19.7146-7159.2000

  18. 18.

    Hut H.M.J., Kampinga H.H., Sibon O.C.M. Hsp70 Protects Mitotic Cells against Heat-induced Centrosome Damage and Division Abnormalities. Mol. Biol. Cell. 2005;16:3776.

    Not in our library10.1091/mbc.e05-01-0038

  19. 19.

    Nylandsted J., Gyrd-Hansen M., Danielewicz A., Fehrenbacher N., Lademann U., Høyer-Hansen M., Weber E., Multhoff G., Rohde M., Jäättelä M. Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J. Exp. Med. 2004;200:425-435.

    Not in our library10.1084/jem.20040531

  20. 20.

    Leist M., Jäättelä M. Four deaths and a funeral: From caspases to alternative mechanisms. Nat. Rev. Mol. Cell Biol. 2001;2:589-598.

    Not in our library10.1038/35085008

  21. 21.

    Kroemer G., Jäättelä M. Lysosomes and autophagy in cell death control. Nat. Rev. Cancer. 2005;5:886-897.

    Not in our library10.1038/nrc1738

  22. 22.

    Zhu D., Dix D.J., Eddy E.M. HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes. Development. 1997;124:3007-3014.

    Not in our library10.1242/dev.124.15.3007

  23. 23.

    Dix D.J., Allen J.W., Collins B.W., Poorman-Allen P., Mori C., Blizard D.R., Brown P.R., Goulding E.H., Strong B.D., Eddy E.M. HSP70-2 is required for desynapsis of synaptonemal complexes during meiotic prophase in juvenile and adult mouse spermatocytes. Development. 1997;124:4595-4603.

    Not in our library10.1242/dev.124.22.4595

  24. 24.

    Govin J., Caron C., Escoffier E., Ferro M., Kuhn L., Rousseaux S., Eddy E.M., Garin J., Khochbin S. Post-meiotic shifts in HSPA2/HSP70.2 chaperone activity during mouse spermatogenesis. J. Biol. Chem. 2006;281:37888.

    Not in our library10.1074/jbc.m608147200

  25. 25.

    Munro S., Pelham H.R.B. An hsp70-like protein in the ER: Identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell. 1986;46:291-300.

    Not in our library10.1016/0092-8674(86)90746-4

  26. 26.

    Hendershot L.M., Valentine V.A., Lee A.S., Morris S.W., Shapiro D.N. Localization of the gene encoding human bip/grp78, the endoplasmic reticulum cognate of the hsp70 family, to chromosome 9q34. Genomics. 1994;20:281-284.

    Not in our library10.1006/geno.1994.1166

  27. 27.

    Gething M.J. Role and regulation of the ER chaperone BiP. Semin. Cell Dev. Biol. 1999;10:465-472.

    Not in our library10.1006/scdb.1999.0318

  28. 28.

    Lindquist S., Craig E.A. The Heat-Shock Proteins. Annu. Rev. Genet. 1988;22:631-677.

    Not in our library10.1146/annurev.ge.22.120188.003215

  29. 29.

    Bukau B., Weissman J., Horwich A. Molecular Chaperones and Protein Quality Control. Cell. 2006;125:443-451.

    Not in our library10.1016/j.cell.2006.04.014

  30. 30.

    Deocaris C.C., Kaul S.C., Wadhwa R. On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones. 2006;11:116-128.

    Not in our library10.1379/csc-144r.1

  31. 31.

    Mizzen L.A., Chang C., Garrels J.I., Welch W.J. Identification, characterization, and purification of two mammalian stres proteins present in mitochondria, grp 75, a member of the hsp 70 family and hsp 58, a homolog of the bacterial groEL protein. J. Biol. Chem. 1989;264:20664-20675.

    Not in our library10.1016/s0021-9258(19)47115-9

  32. 32.

    Panaretou B., Prodromou C., Roe S.M., O’Brien R., Ladbury J.E., Piper P.W., Pearl L.H. ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo. EMBO J. 1998;17:4829-4836.

    Not in our library10.1093/emboj/17.16.4829

  33. 33.

    Dutta R., Inouye M. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem. Sci. 2000;25:24-28.

    Not in our library10.1016/s0968-0004(99)01503-0

  34. 34.

    Meyer P., Prodromou C., Hu B., Vaughan C., Roe S.M., Panaretou B., Piper P.W., Pearl L.H. Structural and functional analysis of the middle segment of Hsp90: Implications for ATP hydrolysis and client protein and cochaperone interactions. Mol. Cell. 2003;11:647-658.

    Not in our library10.1016/s1097-2765(03)00065-0

  35. 35.

    Minami Y., Kawasaki H., Suzuki K., Yahara I. The calmodulin-binding domain of the mouse 90-kDa heat shock protein. J. Biol. Chem. 1993;268:9604-9610.

    Not in our library10.1016/s0021-9258(18)98393-6

  36. 36.

    Meng X., Devin J., Sullivan W.P., Toft D., Baulieu E.E., Catelli M.G. Mutational analysis of Hsp90 alpha dimerization and subcellular localization: Dimer disruption does not impede “in vivo’’ interaction with estrogen receptor. J. Cell Sci. 1996;109:1677-1687.

    Not in our library10.1242/jcs.109.7.1677

  37. 37.

    Soti C., Vermes Á., Haystead T.A.J., Csermely P. Comparative analysis of the ATP-binding sites of Hsp90 by nucleotide affinity cleavage: A distinct nucleotide specificity of the C-terminal ATP-binding site. Eur. J. Biochem. 2003;270:2421-2428.

    Not in our library10.1046/j.1432-1033.2003.03610.x

  38. 38.

    Ali M.M.U., Mark Roe S., Vaughan C.K., Meyer P., Panaretou B., Piper P.W., Prodromou C., Pearl L.H. Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex. Nature. 2006;440:1013-1017.

    Not in our library10.1038/nature04716

  39. 39.

    Prodromou C. The ATPase cycle of Hsp90 drives a molecular clamp’ via transient dimerization of the N-terminal domains. EMBO J. 2000;19:4383-4392.

    Not in our library10.1093/emboj/19.16.4383

  40. 40.

    Cunningham C.N., Krukenberg K.A., Agard D.A. Intra- and intermonomer interactions are required to synergistically facilitate ATP hydrolysis in Hsp90. J. Biol. Chem. 2008;283:21170-21178.

    Not in our library10.1074/jbc.m800046200

  41. 41.

    Hessling M., Richter K., Buchner J. Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nat. Struct. Mol. Biol. 2009;16:287-293.

    Not in our library10.1038/nsmb.1565

  42. 42.

    Åkerfelt M., Morimoto R.I., Sistonen L. Heat shock factors: Integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 2010;11:545-555.

    Not in our library10.1038/nrm2938

  43. 43.

    Richter K., Haslbeck M., Buchner J. The Heat Shock Response: Life on the Verge of Death. Mol. Cell. 2010;40:253-266.

    Not in our library10.1016/j.molcel.2010.10.006

  44. 44.
    Mechanisms of Hsp90 regulation · 2016
    No notice
  45. 45.

    Scroggins B.T., Robzyk K., Wang D., Marcu M.G., Tsutsumi S., Beebe K., Cotter R.J., Felts S., Toft D., Karnitz L., et al. An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function. Mol. Cell. 2007;25:151-159.

    Not in our library10.1016/j.molcel.2006.12.008

  46. 46.

    Kovacs J.J., Murphy P.J.M., Gaillard S., Zhao X., Wu J.T., Nicchitta C.V., Yoshida M., Toft D.O., Pratt W.B., Yao T.P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell. 2005;18:601-607.

    Not in our library10.1016/j.molcel.2005.04.021

  47. 47.

    Bali P., Pranpat M., Bradner J., Balasis M., Fiskus W., Guo F., Rocha K., Kumaraswamy S., Boyapalle S., Atadja P., et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: A novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 2005;280:26729-26734.

    Not in our library10.1074/jbc.c500186200

  48. 48.

    Schopf F.H., Biebl M.M., Buchner J. The HSP90 chaperone machinery. Nat. Rev. Mol. Cell Biol. 2017;18:345-360.

    Not in our library10.1038/nrm.2017.20

  49. 49.

    Wandinger S.K., Suhre M.H., Wegele H., Buchner J. The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90. EMBO J. 2006;25:367-376.

    Not in our library10.1038/sj.emboj.7600930

  50. 50.

    Martínez-Ruiz A., Villanueva L., De Orduña C.G., López-Ferrer D., Ángeles Higueras M., Tarín C., Rodríguez-Crespo I., Vázquez J., Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc. Natl. Acad. Sci. USA. 2005;102:8525-8530.

    Not in our library10.1073/pnas.0407294102

  51. 51.

    Retzlaff M., Stahl M., Eberl H.C., Lagleder S., Beck J., Kessler H., Buchner J. Hsp90 is regulated by a switch point in the C-terminal domain. EMBO Rep. 2009;10:1147-1153.

    Not in our library10.1038/embor.2009.153

  52. 52.

    Taipale M., Krykbaeva I., Koeva M., Kayatekin C., Westover K.D., Karras G.I., Lindquist S. Quantitative analysis of Hsp90-client interactions reveals principles of substrate recognition. Cell. 2012;150:987-1001.

    Not in our library10.1016/j.cell.2012.06.047

  53. 53.

    Miyata Y., Yahara I. Interaction between Casein Kinase II and the 90-kDa Stress Protein, HSP90. Biochemistry. 1995;34:8123-8129.

    Not in our library10.1021/bi00025a019

  54. 54.

    Daturpalli S., Waudby C.A., Meehan S., Jackson S.E. Hsp90 inhibits α-synuclein aggregation by interacting with soluble oligomers. J. Mol. Biol. 2013;425:4614-4628.

    Not in our library10.1016/j.jmb.2013.08.006

  55. 55.

    Evans C.G., Wisén S., Gestwicki J.E. Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro. J. Biol. Chem. 2006;281:33182-33191.

    Not in our library10.1074/jbc.m606192200

  56. 56.

    Jakob U., Lilie H., Meyer I., Buchner J. Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase: Implications for heat shock in vivo. J. Biol. Chem. 1995;270:7288-7294.

    Not in our library10.1074/jbc.270.13.7288

  57. 57.

    Wiech H., Buchner J., Zimmermann R., Jakob U. Hsp90 chaperones protein folding in vitro. Nature. 1992;358:169-170.

    Not in our library10.1038/358169a0

  58. 58.

    Kazlauskas A., Sundström S., Poellinger L., Pongratz I. The hsp90 Chaperone Complex Regulates Intracellular Localization of the Dioxin Receptor. Mol. Cell. Biol. 2001;21:2594-2607.

    Not in our library10.1128/mcb.21.7.2594-2607.2001

  59. 59.

    Csermely P., Schnaider T., Soti C., Prohászka Z., Nardai G. The 90-kDa Molecular Chaperone Family: Structure, Function, and Clinical Applications. A Comprehensive Review. Pharmacol. Ther. 1998;79:129-168.

    Not in our library10.1016/s0163-7258(98)00013-8

  60. 60.

    Koyasu S., Nishida E., Kadowaki T., Matsuzaki F., Iida K., Harada F., Kasuga M., Sakai H., Yahara I. Two mammalian heat shock proteins, HSP90 and HSP100, are actin-binding proteins. Proc. Natl. Acad. Sci. USA. 1986;83:8054-8058.

    Not in our library10.1073/pnas.83.21.8054

  61. 61.

    Sato S., Fujita N., Tsuruo T. Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. USA. 2000;97:10832-10837.

    Not in our library10.1073/pnas.170276797

  62. 62.

    Weis F., Moullintraffort L., Heichette C., Chrétien D., Garnier C. The 90-kDa heat shock protein Hsp90 protects tubulin against thermal denaturation. J. Biol. Chem. 2010;285:9525-9534.

    Not in our library10.1074/jbc.m109.096586

  63. 63.

    Etard C., Roostalu U., Strähle U. Shuttling of the chaperones Unc45b and Hsp90a between the A band and the Z line of the myofibril. J. Cell Biol. 2008;180:1163-1175.

    Not in our library10.1083/jcb.200709128

  64. 64.

    Marzec M., Eletto D., Argon Y. GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim. Biophys. Acta-Mol. Cell Res. 2012;1823:774-787.

    Not in our library10.1016/j.bbamcr.2011.10.013

  65. 65.

    Koch G., Smith M., Macer D., Webster P., Mortara R. Endoplasmic reticulum contains a common, abundant calcium-binding glycoprotein, endoplasmin. J. Cell Sci. 1986;86:217-232.

    Not in our library10.1242/jcs.86.1.217

  66. 66.

    Yang Y., Liu B., Dai J., Srivastava P.K., Zammit D.J., Lefrançois L., Li Z. Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages. Immunity. 2007;26:215-226.

    Not in our library10.1016/j.immuni.2006.12.005

  67. 67.

    Morales C., Wu S., Yang Y., Hao B., Li Z. Drosophila Glycoprotein 93 Is an Ortholog of Mammalian Heat Shock Protein gp96 (grp94, HSP90b1, HSPC4) and Retains Disulfide Bond-Independent Chaperone Function for TLRs and Integrins. J. Immunol. 2009;183:5121-5128.

    Not in our library10.4049/jimmunol.0900811

  68. 68.

    Altieri D.C., Stein G.S., Lian J.B., Languino L.R. TRAP-1, the mitochondrial Hsp90. Biochim. Biophys. Acta-Mol. Cell Res. 2012;1823:767-773.

    Not in our library10.1016/j.bbamcr.2011.08.007

  69. 69.

    Gesualdi N.M., Chirico G., Pirozzi G., Costantino E., Landriscina M., Esposito F. Tumor necrosis factor-associated protein 1 (TRAP-1) protects cells from oxidative stress and apoptosis. Stress. 2007;10:342-350.

    Not in our library10.1080/10253890701314863

  70. 70.

    Masuda Y., Shima G., Aiuchi T., Horie B., Hori K., Nakajo S., Kajimoto S., Shibayama-Imazu T., Nakaya K. Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by β-hydroxyisovalerylshikonin. J. Biol. Chem. 2004;279:42503-42515.

    Not in our library10.1074/jbc.m404256200

  71. 71.

    Siegelin M.D., Dohi T., Raskett C.M., Orlowski G.M., Powers C.M., Gilbert C.A., Ross A.H., Plescia J., Altieri D.C. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J. Clin. Investig. 2011;121:1349-1360.

    Not in our library10.1172/jci44855

  72. 72.

    Cabrera-Hernandez A., Thepparit C., Suksanpaisan L., Smith D.R. Dengue virus entry into liver (HepG2) cells is independent of hsp90 and hsp70. J. Med. Virol. 2007;79:386-392.

    Not in our library10.1002/jmv.20786

  73. 73.

    Pujhari S., Brustolin M., Macias V.M., Nissly R.H., Nomura M., Kuchipudi S.V., Rasgon J.L. Heat shock protein 70 (Hsp70) mediates Zika virus entry, replication, and egress from host cells. Emerg. Microbes Infect. 2019;8:8-16.

    Not in our library10.1080/22221751.2018.1557988

  74. 74.

    Das S., Laxminarayana S.V., Chandra N., Ravi V., Desai A. Heat shock protein 70 on Neuro2a cells is a putative receptor for Japanese encephalitis virus. Virology. 2009;385:47-57.

    Not in our library10.1016/j.virol.2008.10.025

  75. 75.

    Olivia Vega-Almeida T., Salas-Benito M., Ascensión De Nova-Ocampo M., María del Angel R., Santiago Salas-Benito J. Surface proteins of C6/36 cells involved in dengue virus 4 binding and entry. Arch. Virol. 2013;158:1189-1207.

    Not in our library10.1007/s00705-012-1596-0

  76. 76.

    Reyes-del Valle J., Chávez-Salinas S., Medina F., del Angel R.M. Heat Shock Protein 90 and Heat Shock Protein 70 Are Components of Dengue Virus Receptor Complex in Human Cells. J. Virol. 2005;79:4557-4567.

    Not in our library10.1128/jvi.79.8.4557-4567.2005

  77. 77.

    Taguwa S., Yeh M.T., Rainbolt T.K., Nayak A., Shao H., Gestwicki J.E., Andino R., Frydman J. Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease. Cell Rep. 2019;26:906-920.e3.

    Not in our library10.1016/j.celrep.2018.12.095

  78. 78.

    Triantafilou K., Fradelizi D., Wilson K., Triantafilou M. GRP78, a Coreceptor for Coxsackievirus A9, Interacts with Major Histocompatibility Complex Class I Molecules Which Mediate Virus Internalization. J. Virol. 2002;76:633-643.

    Not in our library10.1128/jvi.76.2.633-643.2002

  79. 79.

    Xu T., Lin Z., Wang C., Li Y., Xia Y., Zhao M., Hua L., Chen Y., Guo M., Zhu B. Heat shock protein 70 as a supplementary receptor facilitates enterovirus 71 infections in vitro. Microb. Pathog. 2019;128:106-111.

    Not in our library10.1016/j.micpath.2018.12.032

  80. 80.

    Tsou Y.L., Lin Y.W., Chang H.W., Lin H.Y., Shao H.Y., Yu S.L., Liu C.C., Chitra E., Sia C., Chow Y.H. Heat Shock protein 90: Role in Enterovirus 71 Entry and Assembly and Potential Target for Therapy. PLoS ONE. 2013;8:e77133.

    Not in our library10.1371/journal.pone.0077133

  81. 81.

    Geller R., Andino R., Frydman J. Hsp90 Inhibitors Exhibit Resistance-Free Antiviral Activity against Respiratory Syncytial Virus. PLoS ONE. 2013;8:e56762.

    Not in our library10.1371/journal.pone.0056762

  82. 82.

    Connor J.H., McKenzie M.O., Parks G.D., Lyles D.S. Antiviral activity and RNA polymerase degradation following Hsp90 inhibition in a range of negative strand viruses. Virology. 2007;362:109-119.

    Not in our library10.1016/j.virol.2006.12.026

  83. 83.

    Oliveira A.P., Simabuco F.M., Tamura R.E., Guerrero M.C., Ribeiro P.G.G., Libermann T.A., Zerbini L.F., Ventura A.M. Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells. Virus Res. 2013;177:108-112.

    Not in our library10.1016/j.virusres.2013.07.010

  84. 84.

    Rathore A.P.S., Haystead T., Das P.K., Merits A., Ng M.L., Vasudevan S.G. Chikungunya virus nsP3 & nsP4 interacts with HSP-90 to promote virus replication: HSP-90 inhibitors reduce CHIKV infection and inflammation in vivo. Antivir. Res. 2014;103:7-16.

    Not in our library10.1016/j.antiviral.2013.12.010

  85. 85.

    Chen Y.J., Chen Y.H., Chow L.P., Tsai Y.H., Chen P.H., Huang C.Y.F., Chen W.T., Hwang L.H. Heat shock protein 72 is associated with the hepatitis C virus replicase complex and enhances viral RNA replication. J. Biol. Chem. 2010;285:28183-28190.

    Not in our library10.1074/jbc.m110.118323

  86. 86.

    Ujino S., Yamaguchi S., Shimotohno K., Takaku H. Heat-shock protein 90 is essential for stabilization of the hepatitis C virus nonstructural protein NS3. J. Biol. Chem. 2009;284:6841-6846.

    Not in our library10.1074/jbc.m806452200

  87. 87.

    Manzoor R., Kuroda K., Yoshida R., Tsuda Y., Fujikura D., Miyamoto H., Kajihara M., Kida H., Takada A. Heat shock protein 70 modulates influenza A virus polymerase activity. J. Biol. Chem. 2014;289:7599-7614.

    Not in our library10.1074/jbc.m113.507798

  88. 88.

    Naito T., Momose F., Kawaguchi A., Nagata K. Involvement of Hsp90 in Assembly and Nuclear Import of Influenza Virus RNA Polymerase Subunits. J. Virol. 2007;81:1339-1349.

    Not in our library10.1128/jvi.01917-06

  89. 89.

    Momose F., Naito T., Yano K., Sugimoto S., Morikawa Y., Nagata K. Identification of Hsp90 as a stimulatory host factor involved in influenza virus RNA synthesis. J. Biol. Chem. 2002;277:45306-45314.

    Not in our library10.1074/jbc.m206822200

  90. 90.

    Zhou F., Wan Q., Lu J., Chen Y., Lu G., He M.L. Pim1 Impacts Enterovirus A71 Replication and Represents a Potential Target in Antiviral Therapy. iScience. 2019;19:715-727.

    Not in our library10.1016/j.isci.2019.08.008

  91. 91.

    Katoh H., Kubota T., Kita S., Nakatsu Y., Aoki N., Mori Y., Maenaka K., Takeda M., Kidokoro M. Heat Shock Protein 70 Regulates Degradation of the Mumps Virus Phosphoprotein via the Ubiquitin-Proteasome Pathway. J. Virol. 2015;89:3188-3199.

    Not in our library10.1128/jvi.03343-14

  92. 92.

    Vasconcelos D.Y., Cai X.H., Oglesbee M.J. Constitutive overexpression of the major inducible 70 kDa heat shock protein mediates large plaque formation by measles virus. J. Gen. Virol. 1998;79:2239-2247.

    Not in our library10.1099/0022-1317-79-9-2239

  93. 93.

    Oglesbee M.J., Kenney H., Kenney T., Krakowka S. Enhanced production of morbillivirus gene-specific RNAs following induction of the cellular stress response in stable persistent infection. Virology. 1993;192:556-567.

    Not in our library10.1006/viro.1993.1072

  94. 94.

    García-Dorival I., Wu W., Armstrong S.D., Barr J.N., Carroll M.W., Hewson R., Hiscox J.A. Elucidation of the Cellular Interactome of Ebola Virus Nucleoprotein and Identification of Therapeutic Targets. J. Proteome Res. 2016;15:4290-4303.

    Not in our library10.1021/acs.jproteome.6b00337

  95. 95.
    Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy · 2021
    No notice
  96. 96.

    Waxman L., Whitney M., Pollok B.A., Kuo L.C., Darke P.L. Host cell factor requirement for hepatitis C virus enzyme maturation. Proc. Natl. Acad. Sci. USA. 2001;98:13931-13935.

    Not in our library10.1073/pnas.241510898

  97. 97.

    Geller R., Vignuzzi M., Andino R., Frydman J. Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev. 2007;21:195-205.

    Not in our library10.1101/gad.1505307

  98. 98.

    Kumar P., Gaur P., Kumari R., Lal S.K. Influenza A virus neuraminidase protein interacts with Hsp90, to stabilize itself and enhance cell survival. J. Cell. Biochem. 2019;120:6449-6458.

    Not in our library10.1002/jcb.27935

  99. 99.

    Wang F., Qiu Y., Zhang H.M., Hanson P., Ye X., Zhao G., Xie R., Tong L., Yang D. Heat shock protein 70 promotes coxsackievirus B3 translation initiation and elongation via Akt-mTORC1 pathway depending on activation of p70S6K and Cdc2. Cell. Microbiol. 2017;19:e12725.

    Not in our library10.1111/cmi.12725

  100. 100.

    Dong Q., Men R., Dan X., Chen Y., Li H., Chen G., Zee B., Wang M.H.T., He M.L. Hsc70 regulates the IRES activity and serves as an antiviral target of enterovirus A71 infection. Antivir. Res. 2018;150:39-46.

    Not in our library10.1016/j.antiviral.2017.11.020

  101. 101.

    Macejak D.G., Sarnow P. Association of heat shock protein 70 with enterovirus capsid precursor P1 in infected human cells. J. Virol. 1992;66:1520-1527.

    Not in our library10.1128/jvi.66.3.1520-1527.1992

  102. 102.

    Leone G., Coffey M.C., Gilmore R., Duncan R., Maybaum L., Lee P.W.K. C-terminal trimerization, but not N-terminal trimerization, of the reovirus cell attachment protein is a posttranslational and Hsp70/ATP-dependent process. J. Biol. Chem. 1996;271:8466-8471.

    Not in our library10.1074/jbc.271.14.8466

  103. 103.

    Hirayama E., Atagi H., Hiraki A., Kim J. Heat Shock Protein 70 Is Related to Thermal Inhibition of Nuclear Export of the Influenza Virus Ribonucleoprotein Complex. J. Virol. 2004;78:1263-1270.

    Not in our library10.1128/jvi.78.3.1263-1270.2004

  104. 104.
    Enterovirus A71: virulence, antigenicity, and genetic evolution over the years · 2019
    Not checked
  105. 105.

    Wang R.Y.L., Kuo R.L., Ma W.C., Huang H.I., Yu J.S., Yen S.M., Huang C.R., Shih S.R. Heat shock protein-90-beta facilitates enterovirus 71 viral particles assembly. Virology. 2013;443:236-247.

    Not in our library10.1016/j.virol.2013.05.001

  106. 106.

    Su Y.S., Hsieh P.Y., Li J.S., Pao Y.H., Chen C.J., Hwang L.H. The Heat Shock Protein 70 Family of Chaperones Regulates All Phases of the Enterovirus A71 Life Cycle. Front. Microbiol. 2020;11:1656.

    Not in our library10.3389/fmicb.2020.01656

  107. 107.

    Begum F., Das S., Mukherjee D., Mal S., Ray U. Insight into the tropism of dengue virus in humans. Viruses. 2019;11:1136.

    Not in our library10.3390/v11121136

  108. 108.
    Dengue Fever: Causes, Complications, and Vaccine Strategies · 2016
    No notice
  109. 109.

    Jindadamrongwech S., Thepparit C., Smith D.R. Identification of GRP 78 (BiP) as a liver cell expressed receptor element for dengue virus serotype 2. Arch. Virol. 2004;149:915-927.

    Not in our library10.1007/s00705-003-0263-x

  110. 110.

    Chavez-Salinas S., Ceballos-Olvera I., Reyes-del Valle J., Medina F., del Angel R.M. Heat shock effect upon dengue virus replication into U937 cells. Virus Res. 2008;138:111-118.

    Not in our library10.1016/j.virusres.2008.08.012

  111. 111.

    Taguwa S., Maringer K., Li X., Bernal-Rubio D., Rauch J.N., Gestwicki J.E., Andino R., Fernandez-Sesma A., Frydman J. Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection. Cell. 2015;163:1108-1123.

    Not in our library10.1016/j.cell.2015.10.046

  112. 112.

    Howe M.K., Speer B.L., Hughes P.F., Loiselle D.R., Vasudevan S., Haystead T.A.J. An inducible heat shock protein 70 small molecule inhibitor demonstrates anti-dengue virus activity, validating Hsp70 as a host antiviral target. Antivir. Res. 2016;130:81-92.

    Not in our library10.1016/j.antiviral.2016.03.017

  113. 113.

    Kanlaya R., Thongboonkerd V. Heat Shock Protein 70 (HSP70) Family in Dengue Virus Infection. Regulation of Heat Shock Protein Responses. 2018;395-409.

    Not in our library10.1007/978-3-319-74715-6_16

  114. 114.

    Waters K., Wan H.J., Han L., Xue J., Ykema M., Tao Y.J., Wan X.F. Variations outside the conserved motifs of PB1 catalytic active site may affect replication efficiency of the RNP complex of influenza A virus. Virology. 2021;559:145-155.

    Not in our library10.1016/j.virol.2021.04.001

  115. 115.

    Lamut A., Gjorgjieva M., Naesens L., Liekens S., Lillsunde K.E., Tammela P., Kikelj D., Tomašič T. Anti-influenza virus activity of benzo[d]thiazoles that target heat shock protein 90. Bioorg. Chem. 2020;98:103733.

    Not in our library10.1016/j.bioorg.2020.103733

  116. 116.

    Li G., Zhang J., Tong X., Liu W., Ye X. Heat shock protein 70 inhibits the activity of influenza a virus ribonucleoprotein and blocks the replication of virus In Vitro and In Vivo. PLoS ONE. 2011;6:e16546.

    Not in our library10.1371/journal.pone.0016546

  117. 117.

    Lu R., Zhao X., Li J., Niu P., Yang B., Wu H., Wang W., Song H., Huang B., Zhu N., et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet. 2020;395:565-574.

    Not in our library10.1016/s0140-6736(20)30251-8

  118. 118.
    SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development · 2020
    No notice
  119. 119.

    Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., Huang H., Zhang L., Zhou X., Du C., et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. 2020;180:934-943.

    Not in our library10.1001/jamainternmed.2020.0994

  120. 120.

    Hofving T., Sandblom V., Arvidsson Y., Shubbar E., Altiparmak G., Swanpalmer J., Almobarak B., Elf A.K., Johanson V., Elias E., et al. 177 Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition. Endocr. Relat. Cancer. 2018;26:437-449.

    Not in our library10.1530/erc-18-0509

  121. 121.

    Kubra K.T., Uddin M.A., Akhter M.S., Barabutis N. Hsp90 inhibitors induce the unfolded protein response in bovine and mice lung cells. Cell. Signal. 2020;67:109500.

    Not in our library10.1016/j.cellsig.2019.109500

  122. 122.
    A comprehensive review of COVID-19 characteristics · 2020
    No notice
  123. 123.

    Alreshidi F.S., Ginawi I.A., Hussain M.A., Arif J.M. Piperaquine-and aspirin-mediated protective role of hsp70 and hsp90 as modes to strengthen the natural immunity against potent SARS-CoV-2. Biointerface Res. Appl. Chem. 2021;11:12364-12379.

    Not in our library10.33263/briac114.1236412379

  124. 124.

    Li C., Chu H., Liu X., Chiu M.C., Zhao X., Wang D., Wei Y., Hou Y., Shuai H., Cai J., et al. Human coronavirus dependency on host heat shock protein 90 reveals an antiviral target. Emerg. Microbes Infect. 2020;9:2663-2672.

    Not in our library10.1080/22221751.2020.1850183

  125. 125.

    Sultan I., Howard S., Tbakhi A. Drug Repositioning Suggests a Role for the Heat Shock Protein 90 Inhibitor Geldanamycin in Treating COVID-19 Infection. Res. Sq. 2020.

    Not in our library10.21203/rs.3.rs-18714/v1

  126. 126.
    SARS‐CoV‐2 infection remodels the host protein thermal stability landscape · 2021
    Not checked
  127. 127.

    Seo H.W., Seo J.P., Jung G. Heat shock protein 70 and heat shock protein 90 synergistically increase hepatitis B viral capsid assembly. Biochem. Biophys. Res. Commun. 2018;503:2892-2898.

    Not in our library10.1016/j.bbrc.2018.08.065

  128. 128.

    Niewiarowska J., D’Halluin J.C., Belin M.T. Adenovirus capsid proteins interact with HSP70 proteins after penetration in human or rodent cells. Exp. Cell Res. 1992;201:408-416.

    Not in our library10.1016/0014-4827(92)90290-o

  129. 129.

    Chou C.-K., Wang L.-H., Lin H.-M., Chi C.-W. Glucocorticoid stimulates hepatitis B viral gene expression in cultured human hepatoma cells. Hepatology. 1992;16:13-18.

    Not in our library10.1002/hep.1840160104

  130. 130.

    Zhong M., Zheng K., Chen M., Xiang Y., Jin F., Ma K., Qiu X., Wang Q., Peng T., Kitazato K., et al. Heat-Shock Protein 90 Promotes Nuclear Transport of Herpes Simplex Virus 1 Capsid Protein by Interacting with Acetylated Tubulin. PLoS ONE. 2014;9:e99425.

    Not in our library10.1371/journal.pone.0099425

  131. 131.

    Burch A.D., Weller S.K. Nuclear Sequestration of Cellular Chaperone and Proteasomal Machinery during Herpes Simplex Virus Type 1 Infection. J. Virol. 2004;78:7175.

    Not in our library10.1128/jvi.78.13.7175-7185.2004

  132. 132.

    Cripe T.P., Delos S.E., Estes P.A., Garcea R.L. In vivo and in vitro association of hsc70 with polyomavirus capsid proteins. J. Virol. 1995;69:7807-7813.

    Not in our library10.1128/jvi.69.12.7807-7813.1995

  133. 133.

    Dupzyk A., Williams J.M., Bagchi P., Inoue T., Tsai B. SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum. J. Virol. 2017;91:e00232-17.

    Not in our library10.1128/jvi.00232-17

  134. 134.

    Li Y.H., Tao P.Z., Liu Y.Z., Jiang J.D. Geldanamycin, a Ligand of Heat Shock Protein 90, Inhibits the Replication of Herpes Simplex Virus Type 1 In Vitro. Antimicrob. Agents Chemother. 2004;48:867-872.

    Not in our library10.1128/aac.48.3.867-872.2004

  135. 135.

    Kawashima D., Kanda T., Murata T., Saito S., Sugimoto A., Narita Y., Tsurumi T. Nuclear Transport of Epstein-Barr Virus DNA Polymerase Is Dependent on the BMRF1 Polymerase Processivity Factor and Molecular Chaperone Hsp90. J. Virol. 2013;87:6482-6491.

    Not in our library10.1128/jvi.03428-12

  136. 136.

    Sun X., Barlow E.A., Ma S., Hagemeier S.R., Duellman S.J., Burgess R.R., Tellam J., Khanna R., Kenney S.C. Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism. Proc. Natl. Acad. Sci. USA. 2010;107:3146-3151.

    Not in our library10.1073/pnas.0910717107

  137. 137.

    Hu J., Seeger C. Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase. Proc. Natl. Acad. Sci. USA. 1996;93:1060-1064.

    Not in our library10.1073/pnas.93.3.1060

  138. 138.

    Burch A.D., Weller S.K. Herpes Simplex Virus Type 1 DNA Polymerase Requires the Mammalian Chaperone Hsp90 for Proper Localization to the Nucleus. J. Virol. 2005;79:10740-10749.

    Not in our library10.1128/jvi.79.16.10740-10749.2005

  139. 139.

    Guihur A., Rebeaud M.E., Fauvet B., Tiwari S., Weiss Y.G., Goloubinoff P. Moderate Fever Cycles as a Potential Mechanism to Protect the Respiratory System in COVID-19 Patients. Front. Med. 2020;7:583.

    Not in our library10.3389/fmed.2020.564170

  140. 140.

    Löffler-Mary H., Werr M., Virology R.P. Sequence-specific repression of cotranslational translocation of the hepatitis B virus envelope proteins coincides with binding of heat shock protein Hsc70. Virology. 1997;235:144-152.

    Not in our library10.1006/viro.1997.8689

  141. 141.

    Prange R., Werr M., Löffler-Mary H. Chaperones involved in hepatitis B virus morphogenesis. Biol. Chem. 1999;380:305-314.

    Not in our library10.1515/bc.1999.042

  142. 142.

    Lv Y., Gong L., Wang Z., Han F., Liu H., Lu X., Liu L. Curcumin inhibits human cytomegalovirus by downregulating heat shock protein 90. Mol. Med. Rep. 2015;12:4789-4793.

    Not in our library10.3892/mmr.2015.3983

  143. 143.

    Basha W., Kitagawa R., Uhara M., Imazu H., Uechi K., Tanaka J. Geldanamycin, a potent and specific inhibitor of Hsp90, inhibits gene expression and replication of human cytomegalovirus. Antivir. Chem. Chemother. 2005;16:135-146.

    Not in our library10.1177/095632020501600206

  144. 144.

    Devireddy L.R., Kumar K.U., Pater M.M., Pater A. BAG-1, a novel Bcl-2-interacting protein, activates expression of human JC virus. J. Gen. Virol. 2000;81:351-357.

    Not in our library10.1099/0022-1317-81-2-351

  145. 145.

    Takahashi N., Sasaki R., Takahashi J., Takayama S., Reed J.C., Andoh T. BAG-1M, an isoform of Bcl-2-interacting protein BAG-1, enhances gene expression driven by CMV promoter. Biochem. Biophys. Res. Commun. 2001;286:807-814.

    Not in our library10.1006/bbrc.2001.5473

  146. 146.

    Ikebe E., Kawaguchi A., Tezuka K., Taguchi S., Hirose S., Matsumoto T., Mitsui T., Senba K., Nishizono A., Hori M., et al. A novel HSP90 inhibitor, 17-DMAG, induces Tax down-regulation and its oral administration to ATL-model mice intervenes against the infiltration property of the ATL-like lymphocytes and provides extended survival period. Retrovirology. 2014;11:P44.

    Not in our library10.1186/1742-4690-11-s1-p44

  147. 147.

    Shim H.Y., Quan X., Yi Y.S., Jung G. Heat shock protein 90 facilitates formation of the HBV capsid via interacting with the HBV core protein dimers. Virology. 2011;410:161-169.

    Not in our library10.1016/j.virol.2010.11.005

  148. 148.

    Kim W.H., Hong F., Jaruga B., Hu Z., Fan S., Liang T.J., Gao B. Additive activation of hepatic NF-kappaB by ethanol and hepatitis B protein X (HBX) or HCV core protein: Involvement of TNF-alpha receptor 1-independent and -dependent mechanisms. FASEB J. 2001;15:2551-2553.

    Not in our library10.1096/fj.01-0217

  149. 149.

    Dogrammatzis C., Waisner H., Kalamvoki M. “Non-Essential” Proteins of HSV-1 with Essential Roles In Vivo: A Comprehensive Review. Viruses. 2021;13:17.

    Not in our library10.3390/v13010017

  150. 150.

    Li F., Jin F., Wang Y., Zheng D., Liu J., Zhang Z., Wang R., Dong D., Zheng K., Wang Y. Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly. J. Biochem. 2018;164:397-406.

    Not in our library10.1093/jb/mvy066

  151. 151.
    Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development · 2020
    No notice
  152. 152.

    Chevaliez S. Strategies for the improvement of HCV testing and diagnosis. Expert Rev. Anti-Infect. Ther. 2019;17:341-347.

    Not in our library10.1080/14787210.2019.1604221

  153. 153.

    Braga A.C.S., Carneiro B.M., Batista M.N., Akinaga M.M., Rahal P. Inhibition of hepatitis C virus using siRNA targeted to the virus and Hsp90. Cell Stress Chaperones. 2017;22:113.

    Not in our library10.1007/s12192-016-0747-8

  154. 154.

    Khachatoorian R., Arumugaswami V., Ruchala P., Raychaudhuri S., Maloney E.M., Miao E., Dasgupta A., French S.W. A cell-permeable hairpin peptide inhibits hepatitis C viral nonstructural protein 5A-mediated translation and virus production. Hepatology. 2012;55:1662-1672.

    Not in our library10.1002/hep.25533

  155. 155.

    Gonzalez O., Fontanes V., Raychaudhuri S., Loo R., Loo J., Arumugaswami V., Sun R., Dasgupta A., French S.W. The heat shock protein inhibitor Quercetin attenuates hepatitis C virus production. Hepatology. 2009;50:1756-1764.

    Not in our library10.1002/hep.23232

  156. 156.

    Lim Y.S., Shin K.S., Oh S.H., Kang S.M., Won S.J., Hwang S.B. Nonstructural 5A protein of hepatitis C virus regulates heat shock protein 72 for its own propagation. J. Viral Hepat. 2012;19:353-363.

    Not in our library10.1111/j.1365-2893.2011.01556.x

  157. 157.

    Khachatoorian R., Ganapathy E., Ahmadieh Y., Wheatley N., Sundberg C., Jung C.L., Arumugaswami V., Raychaudhuri S., Dasgupta A., French S.W. The NS5A-binding heat shock proteins HSC70 and HSP70 play distinct roles in the hepatitis C viral life cycle. Virology. 2014;454–455:118-127.

    Not in our library10.1016/j.virol.2014.02.016

  158. 158.

    Kim M.G., Moon J.S., Kim E.J., Lee S.H., Oh J.W. Destabilization of PDK1 by Hsp90 inactivation suppresses hepatitis C virus replication through inhibition of PRK2-mediated viral RNA polymerase phosphorylation. Biochem. Biophys. Res. Commun. 2012;421:112-118.

    Not in our library10.1016/j.bbrc.2012.03.126

  159. 159.

    Okamoto T., Nishimura Y., Ichimura T., Suzuki K., Miyamura T., Suzuki T., Moriishi K., Matsuura Y. Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90. EMBO J. 2006;25:5015-5025.

    Not in our library10.1038/sj.emboj.7601367

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