Geldanamycin, a Potent and Specific Inhibitor of Hsp90, Inhibits Gene Expression and Replication of Human Cytomegalovirus

Basha, Walid; Kitagawa, Ryo; Uhara, Miho; Imazu, Hiromi; Uechi, Kouhei; Tanaka, Junji

doi:10.1177/095632020501600206

Cited by 47 publications

(47 citation statements)

References 63 publications

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“…Furthermore, it is implicated in regulation of proteasomal degradation orchestrated by Hsp90 (37). There is increasing evidence that chaperone activity is required for efficient growth of viruses (23,24,(38)(39)(40)(41)(42)(43). Our results emphasize the importance of BAG3, a regulator of chaperone activity, in the life cycle of herpesviruses, raising the interesting possibility that co-chaperones might function to control replication of other animal viruses.…”

Section: Discussionsupporting

confidence: 55%

The co-chaperone BAG3 regulates Herpes Simplex Virus replication

Kyratsous

Silverstein

2008

Proc. Natl. Acad. Sci. U.S.A.

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Viruses as obligate intracellular parasites use host cell proteins to ensure efficient replication and spread. Cellular proteins are required for several stages of a virus life cycle. Here, we identify BAG3, a co-chaperone, as a regulator of herpes virus immediate early gene expression. We report that a herpes simplex virus lacking the gene encoding a potent transcriptional activator, ICP0, is compromised for replication in cells silenced for BAG3 in a multiplicity of infectiondependent manner. We also show a requirement for BAG3 to augment virus gene expression and demonstrate that the co-chaperone acts independently of promyelocytic leukemia to increase herpes simplex virus replication.Hsc70 ͉ HSV ͉ ICP0 ͉ VZV P roductive infection by herpes simplex virus (HSV) is temporally regulated in a tightly coordinated cascade. Control of this process involves a complex and largely unknown network of interactions between host-and virus-encoded proteins. HSV genes are classified as immediate early (␣), early (␤), and late (␥) based on their temporal expression during productive replication. A virion protein (VP16) interacts with the host transcription machinery to initiate expression from ␣ genes. Three of the ␣ proteins (ICP0, ICP4, and ICP27) cooperatively regulate expression of all classes of virus genes (1).ICP0 is a C 3 HC 4 RING finger containing nuclear phosphoprotein with an apparent molecular mass of 110 kDa (2). Virus mutants lacking the ICP0 gene have an increased particle to pfu ratio, substantially lower yield, and decreased levels of ␣ gene expression. These properties manifest themselves in a multiplicity of infection (moi) and cell type-dependent manner (3, 4). ICP0 behaves as a promiscuous activator of viral and cellular genes (5-7), stimulating expression, at least in part, indirectly by hijacking host activators to use in virus replication and/or by helping the virus bypass innate cellular repression pathways (8, 9).ICP0 also functions as an E3 ubiquitin ligase to target a growing list of host proteins for proteasomal degradation (10)(11)(12)(13)(14). Through this activity, ICP0 promotes degradation of components of nuclear domain 10 (ND10) bodies, including the promyelocytic leukemia (PML) proteins, Sp100 and Daxx. Incoming HSV genomes are decorated with components of ND10s before ICP0-directed dissociation of these bodies and degradation of their constituents occurs (15). Proteins that normally reside within these structures are implicated in silencing of herpesvirus genomes (16)(17)(18)(19). Therefore, ICP0-mediated degradation of host proteins may disrupt silencing of HSV genes and enable efficient virus gene expression. The RING finger of ICP0 is required for degradation of ND10 localized proteins and for its transactivation activity (20).After infection with HSV, virus-induced chaperone-enriched (VICE) nuclear bodies form adjacent to virus replication/ transcription foci. The presence of ICP0 facilitates formation of Hsc70 containing domains and results in augmentation of virus growth (21-23).Unl...

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Section: Discussionsupporting

confidence: 55%

The co-chaperone BAG3 regulates Herpes Simplex Virus replication

Kyratsous

Silverstein

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Hsp90 inhibitors may also inhibit viral replication at least partially via their effects on cellular proteins. Of particular interest to our findings here, geldanamycin has been reported to inhibit HCMV replication by disruption of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway, thereby leading to decreased expression levels of the viral IE genes (95). However, in contrast to the previous study (95), we did not find that 17-DMAG treatment affects expression of HCMV IE1 protein, or its ability to activate the UL44 early lytic gene, during infection of primary human fibroblasts.…”

Section: Discussionmentioning

confidence: 91%

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Sun

Bristol

Iwahori

et al. 2013

J Virol

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H uman herpesviruses are enveloped viruses containing relatively large, double-stranded DNA genomes. Although all herpesviruses experience both latent and lytic stages of infection, they are grouped into three separate families (alpha-, beta-, and gammaherpesviruses) according to differences in sequence homology and cellular tropisms. The alphaherpesviruses, which comprise herpes simplex virus 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), cause recurrent skin lesions and meningitis (1, 2). Human cytomegalovirus (HCMV), human herpesviruses 6A and 6B (HHV6), and human herpesvirus 7 (HHV7) are betaherpesviruses, which cause severe disease in patients with compromised immune function (3, 4). The gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), which are causally associated with mononucleosis (EBV) as well as a variety of human cancers (5, 6).Each of the eight human herpesviruses encodes a protein kinase (PK) with discernible homology in amino acid sequences and positional similarity in their respective viral genomes. These related protein kinases, termed the conserved herpesvirus protein kinases (CHPKs), are important for viral replication and infection (7-13). They play important roles in multiple processes, including gene expression (8,11,14), viral DNA replication (11,(15)(16)(17), capsid nuclear egress (7,11,18,19), and the DNA damage response (20, 21). For example, EBV PK (the product of the BGLF4 gene) phosphorylates a number of different viral and cellular proteins, including the viral DNA polymerase processivity factor BMRF1 (7,(22)(23)(24); the latent viral proteins EBNA1 (25), EBNA2 (26), and EBNA LP (27); the EBV immediate early (IE) protein BZLF1 (28); the cell cycle regulatory proteins p27 (29) and pRB (30); nuclear lamin A/C (7, 31); and interferon regulatory factor 3 (IRF3) (32). In addition, EBV PK may upregulate the expression of two viral proteins important for nuclear egress, BFRF1 and BFLF2 (11,33). Both EBV PK and the homologous HCMV kinase, UL97, greatly enhance but are not absolutely required for the release of infectious viral particles in vitro and appear to be intimately involved in the pathogenesis associated with viral infections in vivo (34,35). Although maribavir, an inhibitor of HCMV UL97, failed a phase III clinical trial in bone marrow transplant patients (36) (possibly due to insufficient dosing), CHPKs nevertheless remain very promising targets for development of novel antiviral therapeutics.Two guanine nucleoside analogues, ganciclovir (GCV) and acyclovir (ACV), have been used frequently to inhibit replication of various human herpesviruses by targeting viral DNA polymerases (37-40). UL97 mediates the first step of GCV and ACV phosphorylation (41-43). Since the triphosphorylated forms of GCV and ACV are much better substrates for herpesvirus DNA polymerases than cellular DNA polymerases, GCV and ACV inhibit viral DNA replication more effectively than cellular DNA replication (44,45). It was recently found that EBV PK is req...

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“…Indeed, several unrelated viruses are reported to encode proteins that depend on Hsp90 for their activity (Hu et al 1997;Hung et al 2002;Li et al 2004;Basha et al 2005;Burch and Weller 2005;Janin 2005;Kampmueller and Miller 2005;Okamoto et al 2006). Accordingly, chaperone inhibitors may hold promise as broad antiviral agents.…”

Section: Molecular Chaperones As Novel Antiviral Targetsmentioning

confidence: 99%

“…However, the role of molecular chaperones in viral protein folding has not been extensively explored. Hsp90 is the only chaperone with specific pharmacological inhibitors; these inhibitors of Hsp90 have been shown to reduce the replication of several viruses in vitro (Hu et al 1997;Hung et al 2002;Li et al 2004;Basha et al 2005;Burch and Weller 2005;Janin 2005;Kampmueller and Miller 2005;Okamoto et al 2006). For most of these viruses, it is unclear whether the observed inhibitory effect is directly related to the folding of viral proteins by Hsp90, or due to pleiotropic effects on viral replication arising from inhibition of cellular Hsp90 targets.…”

mentioning

confidence: 99%

“…Several lines of evidence suggest that viral proteins, like cellular proteins, bind to chaperones or are dependent on chaperone function for folding and assembly (Hu et al 1997;Braakman and van Anken 2000;Hong et al 2001;Hung et al 2002;Li et al 2004;Basha et al 2005;Burch and Weller 2005;Kampmueller and Miller 2005;Mayer 2005). However, the role of molecular chaperones in viral protein folding has not been extensively explored.…”

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confidence: 99%

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Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance

Geller¹,

Vignuzzi²,

Andino³

et al. 2007

Genes Dev.

256

272

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The genome diversity of RNA viruses allows for rapid adaptation to a wide variety of adverse conditions. Accordingly, viruses can escape inhibition by most antiviral compounds targeting either viral or host factors. Here we exploited the capacity of RNA viruses for rapid adaptation to explore the evolutionary constraints of chaperone-mediated protein folding. We hypothesized that inhibiting a host molecular chaperone required for folding of a viral protein would force the virus to evolve an alternate folding strategy. We identified the chaperone Hsp90 as an essential factor for folding and maturation of picornavirus capsid proteins. Pharmacological inhibition of Hsp90 impaired the replication of poliovirus, rhinovirus, and coxsackievirus in cell culture. Strikingly, anti-Hsp90 treatment did not yield drug-resistant viruses, suggesting that the complexity of capsid folding precludes the emergence of alternate folding pathways. These results reveal tight evolutionary constraints on chaperone-mediated protein folding, which may be exploited for viral inhibition in vivo. Indeed, Hsp90 inhibitors drastically reduced poliovirus replication in infected animals without the emergence of drug-resistant escape mutants. We propose that targeting folding of viral proteins may provide a general antiviral strategy that is refractory to development of drug resistance.[Keywords: Evolution; protein folding; Hsp90; drug resistance; antiviral; picornavirus] Supplemental material is available at http://www.genesdev.org.

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Geldanamycin, a Potent and Specific Inhibitor of Hsp90, Inhibits Gene Expression and Replication of Human Cytomegalovirus

Cited by 47 publications

References 63 publications

The co-chaperone BAG3 regulates Herpes Simplex Virus replication

The co-chaperone BAG3 regulates Herpes Simplex Virus replication

Hsp90 Inhibitor 17-DMAG Decreases Expression of Conserved Herpesvirus Protein Kinases and Reduces Virus Production in Epstein-Barr Virus-Infected Cells

Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance

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