Proteostasis in Viral Infection: Unfolding the Complex Virus–Chaperone Interplay

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Ranen Aviner1 and Judith Frydman1,2

1Department of Biology, Stanford University, Stanford, California 94305 2Department of Genetics, Stanford University, Stanford, California 94305 Correspondence: [email protected]

Viruses are obligate intracellular parasites that rely on their hosts for protein synthesis, genome replication, and viral particle production. As such, they have evolved mechanisms to divert host resources, including molecular chaperones, facilitate folding and assembly of viral proteins, stabilize complex structures under constant mutational pressure, and modulate signaling pathways to dampen antiviral responses and prevent premature host death. Biogenesis of viral proteins often presents unique challenges to the proteostasis network, as it requires the rapid and orchestrated production of high levels of a limited number of multifunctional, multidomain, and aggregation-prone proteins. To overcome such challenges, viruses interact with the folding machinery not only as clients but also as regulators of chaperone expression, function, and subcellular localization. In this review, we summarize the main types of interactions between viral proteins and chaperones during infection, examine evolutionary aspects of this relationship, and discuss the potential of using chaperone inhibitors as broad-spectrum antivirals.

ost proteins must fold properly before they synthesis, folding, trafﬁcking, and assembly of Mcan perform their functions, and many replication complexes (RCs) and viral particles; require assistance of molecular chaperones as modulators, they regulate the activity and to achieve a native conformation. Considering subcellular localization of chaperones, affecting the complexity of viral proteins, it is not surpris- other interactors involved in pathogenesis, im- ing that they, too, depend on chaperones for mune response, and apoptosis. These complex proper folding and function. Although some interactions have likely evolved as a result of the viruses encode their own chaperones, the vast unique features of viral proteins, which are often majority—from bacterial, plant, and inverte- expressed as multifunctional multidomain pre- brate to human viruses—rely on chaperones ex- cursors. Positive-strand RNA viruses produce a pressed by the host cell, most notably members single polyprotein that requires co- and post- of the so-called heat shock protein (HSP) family translational processing into mature individual (e.g., Hsp70, Hsp90, and Hsp60) (Table 1). As proteins, rendering it prone to misfolding and clients, viral proteins require chaperones for aggregation (Nagata et al. 1987; Mah et al. 1990;

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R. Aviner and J. Frydman

Table 1. Major chaperone systems in mammalian cells Cellular Chaperones compartment Major functions Cofactors and functions HSP70 system Hsc70, constitutive (HSPA8) Cytosol Folding and stabilization of Hsp40s (DnaJs) stimulate Hsp70, inducible (HSPA1A/B) Cytosol newly synthesized Hsp70 ATPase activity; BiP/Grp78 (HSPA5) ER proteins; assembly and nucleotide exchange Mortalin (HSPA9) Mitochondria disassembly of multimeric factors, for example, complexes; import into ER Bag1-5, Bap (SIL1), and and mitochondria Grp170 (HYOU1) stimulate ADP release; HSPBP1 inhibits chaperone activity by interfering with ATP binding HSP90 system Hsp90 (HSP90AA1/AB1) Cytosol Stabilization, maturation, and Hop (STIP1) mediates Grp94/endoplasmin ER activation of enzymatic interaction of Hsp70 and (HSP90B1) complexes (e.g., kinases, Hsp90; p23 (PTGES3), receptors); mediates Cdc37 stabilize Hsp90 intracellular signaling interactions with clients Chaperonins TRiC/CCT (TCP1, CCT2-8) Cytosol Folding; prevention of Prefoldin cofactor guides aggregation clients to TRiC/CCT Hsp60 (HSPD1) Mitochondria Folding of proteins imported Hsp10 (HSPE1) sequesters into mitochondria substrates in Hsp60 cavities Others Calnexin (CANX) ER Folding and refolding of Calreticulin (CALR) secretory proteins Protein disulﬁde isomerase ER Rearrangement of disulﬁde (PDI) bonds Peptidyl-prolyl cis–trans Cytosol, ER, Catalysis of energetically isomerase (PPI) mitochondria unfavorable cis-to-trans isomerization ER, Endoplasmic reticulum; Bap, BiP-associated protein.

Hung et al. 2002; Geller et al. 2007). Capsid (Crowder and Kirkegaard 2005; Lauring et al. proteins that enclose the viral genome in virions 2013). are particularly sensitive to misassembly, as they The rate of protein production in virus-in- must be folded into soluble conformations that fected cells is another source of pressure on the form structures rigid enough to protect the ge- proteostasis machinery. Rapidly replicating lytic nome against harsh extracellular environments, viruses reprogram their hosts to produce large yet ﬂexible enough to readily disassemble upon amounts of a small number of viral proteins entry into the cell and allow replication (Ross- within a short period of time, likely taxing the mann 1984). Additionally, the high mutation capacity of chaperones required to fold them. rate of viruses inevitably leads to frequent emer- This may explain why so many viruses induce gence of protein variants with compromised a shutoff of host translation (Stern-Ginossar function or stability, and chaperones can help et al. 2018): not only to curtail antiviral re- buffer the deleterious effects of such mutations sponses, but also to minimize competition over

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Proteostasis in Viral Infection

a limited chaperone pool. In contrast, viruses dent stress signaling. For example, herpes and associated with chronic infection replicate polyomaviruses express viral proteins that inter- slowly over a long time and may, thus, have low- act with TATA- or CCAAT-binding transcrip- er demand for chaperones. In these, chaperones tion factors (Lum et al. 1992; Damania et al. are still used for folding but also to dampen an- 1998), whereas adenoviruses encode for a pro- tiviral responses, suppress premature apoptosis, tein that allows Hsp70 messenger RNA (mRNA) and remodel the cellular environment to ensure to escape the virus-induced block on nuclear persistent infection. Both infection strategies in- export (Moore et al. 1987). volve induction of chaperone expression either Taken together, these observations suggest as a direct consequence of the febrile response that the biogenesis of viral proteins imposes a (Mayer 2005; Kim and Oglesbee 2012) or be- significant and uniquely regulated burden on cause of more selective mechanisms encoded the cellular proteostasis network, highlighting by viral genomes. When unfolded proteins ac- the importance of chaperones in infection. The cumulate, Hsp70 (Shi et al. 1998) and Hsp90 next few sections review the interplay between (Zou et al. 1998) are titrated away from heat viral proteins and chaperones at distinct steps of shock factor 1 (HSF1), allowing it to activate the replication cycle, from entry and disassem- chaperone transcription (Kijima et al. 2018). bly to synthesis and release of viral particles Therefore, one of the ways viruses can induce (summarized in Fig. 1). As cells express multiple chaperone expression is simply by mass produc- constitutive and stress-inducible isoforms of tion of nascent or misfolded proteins. Alterna- most chaperones, generic family names (e.g., tively, viral proteins can directly activate specific Hsp70) are used herein for the sake of simplicity, promoters or otherwise regulate HSF1-indepen- unless the mention of a specific isoform is mech-

AB Internalization Uncoating Egress Prosurvival Assembly signaling Chaperone Translation, folding Viral RNA

Reverse Viral capsid transcription

Replication Viral envelope Aggregation Viral polymerase Proteasomal degradation Compartment remodeling Viral protease Nuclear Protease-competent import Transcription VICE domains conformation ER Cytoplasm Nucleus Cytoplasm

Figure 1. Roles of chaperones in the major steps of the viral replication cycle. (A) Cell surface chaperones interact with viral envelope or capsid proteins and facilitate internalization. Intracellular chaperones can then destabilize the nucleocapsid conformation to release the viral genome. By binding to internal ribosome entry sites (IRESs) or nascent polypeptide chains, chaperones can stimulate translation, prevent aggregation and proteasome-mediated degradation, and facilitate folding into a protease-competent conformation for subsequent processing by viral proteases. Through direct interactions with viral structural or nonstructural proteins, chaperones can maintain an active conformation of reverse transcriptases (RTs) and support nuclear import of viral proteins and genomes. (B) To prevent premature apoptosis of host cells, viruses hijack nuclear and mitochondrial chaperone-modulated prosurvival pathways. Chaperones facilitate transcription and replication by stabilizing viral polymerases and activating promoter regions either directly or indirectly. Some viruses remodel the endoplasmic reticulum (ER) membrane or the nucleoplasm to form replication compartments or specialized virus-induced chaperone- enriched (VICE) domains that serves as hubs of viral protein quality control. Finally, chaperones assist in the multimeric assembly of nucleocapsids and can be packaged into and released with infectious particles.

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anistically or functionally informative (e.g., en- brane penetration and subsequent translocation. doplasmic reticulum [ER]-resident Hsp70, BiP). First, capsid protein VP1 pentamers are destabilized by the protein disulfide reductase/isomerase function of DNAJC10/ERdj5, PDIA1/PDI, ROLES OF CHAPERONES IN THE and PDIA3/ERdj57, exposing the more hydro- REPLICATION CYCLE phobic minor coat proteins (CPs) VP2/3 (Schel- haas et al. 2007; Inoue et al. 2015). Then, BiP and Entry and Disassembly DNAJB11 hold the virus in atranslocation-com- Most viruses enter host cells through either re- petent state (Goodwin et al. 2011), which is ceptor-mediated endocytosis or plasma mem- further stabilized by binding to ER membrane brane fusion (Yamauchi and Helenius 2013). complex 1 (EMC1), preventing premature un- Multiple reports have shown that chaperones coating (Bagchi et al. 2016). The stabilized inter- can localize to the cell surface and act as corecep- mediate interacts with a cytosolic extraction tors aiding virus entry, probably by mediating complex comprised of Hsp70 and cochaperone conformational changes in the viral capsid. Non- SGT1/SGTA, which is recruited to membrane enveloped double-stranded RNA (dsRNA) vi- penetration sites through interactions with ruses of the reovirus family are internalized DNAJB12, DNAJB14, and DNAJC18 (Bagchi and disassembled through ATP-dependent et al. 2015). For translocation to be completed, interactions between Hsp70 and their capsid pro- nucleotide exchange factors (NEFs) HYOU1/ teins. Preincubation of viral particles with re- Grp170 and Bag2 or Hsp105/HSPH1 release combinant Hsp70 or antibodies against Hsp70 the capsid from BiP (Inoue and Tsai 2015) and prevented rotavirus internalization (Guerrero et Hsp70 (Dupzyk and Tsai 2018), respectively. al. 2002; Zarate et al. 2003; Perez-Vargas et al. After crossing the cellular membrane barrier 2006), and Hsp70 depletion impaired reovirus during cell entry, most animal viruses must un- disassembly into transcriptionally active parti- dergo further disassembly before initiating viral cles (Ivanovic et al. 2007). In cucumber necrosis gene expression. In many cases, these disassem- virus, Hsp70 was found to directly alter capsid bly mechanisms remain poorly defined but like- conformation, as determined by electron mi- ly also involve the proteostasis machinery. For croscopy (Alam and Rochon 2017). A similar instance, Hsp70 plays a key role in the final step extracellular interaction with Hsp70 was report- in disassembly of reovirus outer capsid during ed for positive-strand RNAviruses of the flavivi- or soon after membrane penetration. ATP and rus family, for example, hepatitis C virus (HCV) Hsp70 are required for cytoplasmic release of the (Parent et al. 2009; Khachatoorian et al. 2014), central, δ fragment of membrane penetration Japanese encephalitis virus (JEV) (Das et al. protein μ1 to yield the transcriptionally active 2009), and dengue virus (DENV) (Reyes-Del viral core particle to prepare the entering particle Valle et al. 2005). DENV also uses Hsp90, BiP, for gene expression and replication (Ivanovic et and several DnaJ proteins for internalization, al. 2007). demonstrating that this process is not exclusive to Hsp70 (Reyes-Del Valle et al. 2005; Cabrera- Nuclear Import Hernandez et al. 2007; Taguwa et al. 2015). One of the best-studied examples for chap- Following internalization and disassembly, nu- erone-mediated virion disassembly is that of clear-replicating viruses must deliver viral par- simian virus 40 (SV40), a nonenveloped dsDNA ticles or individual proteins into the nucleus. In polyomavirusthat is endocytosed and transport- influenza, a negative-strand RNA virus, both ed intact into the ER. There, it undergoes un- the RNA-dependent RNA polymerase and viral coating to allow a smaller viral particle to enter genome require chaperone-mediated nuclear the cytoplasm and then the nucleus. In the ER, import. Direct interaction of Hsp90 with poly- host-induced conformational changes render merase subunits PB1 and PB2 is needed for both the virus more hydrophobic and allow its mem- import and assembly of the polymerase complex

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Proteostasis in Viral Infection

(Momose et al. 2002; Naito et al. 2007). Hsp90 wise interfere with infection (Mathew et al. 2009; inhibition prevented nuclear relocalization and Bastian et al. 2010). enhanced the degradation of polymerase subunits (Chase et al. 2008). In addition, viral ge- Folding and Assembly of Viral Polymerases nome import is supported by Hsp70 cofactor and Other Nonstructural Proteins DNAJB1/Hdj1, which bridges between the nucleoprotein and importin α (Batra et al. 2016). One of the better-characterized roles of chaper- By binding to DNAJB1, the nucleoprotein also ones in viral infection is stabilization and ac- displaces and activates DNAJC3/P58(IPK), tivation of viral polymerase components, influ- which in turn inhibits dsRNA-dependent pro- encing both transcription and replication (Fig. tein kinase (PKR), a key regulator of the antiviral 2A). The human papillomavirus (HPV) encodes immune response (Sharma et al. 2011). two proteins, E2 and E1, which bind and un- Both Hsp90 and Hsp70 are also involved in wind the origin of replication (oriP), respective- the nuclear localization of DNA-dependent ly. E2 recruits E1 but also inhibits unwinding; by DNA polymerases of multiple herpesviruses. displacing E2, Hsp70 and cofactors DNAJA1 Epstein–Barr virus (EBV) BMRF1, herpes sim- and DNAJB1 enhance E1 activity and promote plex (HSV) UL30, and varicella zoster virus viral replication (Liu et al. 1998; Lin et al. 2002). (VZV) ORF29p, three proteins involved in viral Similarly, interaction of HSV origin-binding replication, were shown to depend on Hsp90 for UL9 with Hsp70 and DNAJA3/hTid1 supports nuclear import (Burch and Weller 2005; Kyrat- its multimeric assembly on oriP (Eom and Leh- sous and Silverstein 2007; Kawashima et al. man 2002; Tanguy Le Gac and Boehmer 2002). 2013). In addition to Hsp90, the latter two re- In Kaposi’s sarcoma–associated herpesvirus quire a complex consisting of Hsp70 and co- (KSHV), Hsp70 inhibition prevented RC forma- chaperone Bag3 (Li et al. 2004; Burch and Weller tion and recruitment of RNA polymerase II to 2005; Kyratsous and Silverstein 2007, 2008). In the viral genome, leading to reduced transcrip- human immunodeficiency virus (HIV), which tion (Baquero-Pérez and Whitehouse 2015). undergoes cytoplasmic reverse transcription Hsp70 also maintains the stability of RCs in followed by formation of preintegration com- HCV (Chen et al. 2010) and JEV (Ye et al. plexes (PICs), DNAJB6/Hsj2 facilitates nuclear 2013) through direct interactions with polymer- import of PIC through interactions with viral ase components. In measles, Hsp70 acts as a po- protein Vpx. Overexpression of DNAJB6/Hsj2 lymerase processivity factor by loosening bind- enhanced PIC import, whereas depletion or ing and allowing the polymerase to move to the expression of a nuclear-localization mutant re- next template, and its overexpression in micewas duced it (Cheng et al. 2008). Furthermore, associated with higher viral load and mortality Hsp70 can compete with viral protein Vpr for rates (Zhang et al. 2005; Carsillo et al. 2006). binding to importin α and either block import in In HIV, transcription and replication are stimu- wild-type virus or facilitate it in Vpr-deficient lated by mitochondrial Hsp70 and DNAJB1 virus (Agostini et al. 2000). through stabilization of the viral Nef protein Viral proteins can also drive the nuclear re- (Kumarand Mitra 2005; Kumaret al. 2011; Shel- localization of chaperones. During earlystages of ton et al. 2012). They are further supported by HSV infection, viral protein ICP22 is responsible Hsp70, Hsp90, and the Hsp90 cochaperone for the formation of discrete nuclear foci called Cdc37 through stabilization of CDK9/Cyclin virus-induced chaperone-enriched (VICE) do- T1, which is required for phosphorylation and mains near viral RCs. These chaperone-rich activation of transcription by HIV Tat protein domains consist of protein quality control com- (O’Keeffe et al. 2000). Hsp90, Hsp70, and Bag1 ponents, including Hsp90, Hsp70, small HSPs, were even found to independently interact with and active 20S proteasomes, and are thought to HIVand human cytomegalovirus (HCMV) viral facilitate viral replication by sequestering mis- promoters, potentially regulating viral transcrip- folded or unwanted proteins that would other- tion (Niyaz et al. 2003; Vozzolo et al. 2010).

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A Folding Native Activation Chaperone intermediate polymerase Replication Folding Assembly complex into RC Capsid precursor Degradation Conformational maintenance Viral protease B Hsp70

p23 Assembly

Hsp90 Mature ATP ADP ATP ADP capsid

Figure 2. Distinct functions of chaperones in viral replication and capsid assembly. (A) Chaperones (e.g., Hsp70, TRiC/CCT, and Hsp90) assist the folding of nascent viral polymerases into native conformations and prevent their proteasomal degradation. Native polymerases are then guided by chaperones to the appropriate cellular compartments and assembled into a replication complex (RC). Following assembly, some polymerases require chaperones for both activation and continued conformational maintenance. (B) Role of Hsp90 in picornavirus capsid maturation exempliﬁes chaperone-assisted virion assembly. The poliovirus capsid precursor is bound cotranslationally by Hsp70 and then folded by Hsp90 and cochaperone p23 into a conformation that allows proteolytic processing by the viral protease. Following cleavage, capsid subunits can be assembled in successive steps leading to the mature virion containing the viral genome.

Many viral polymerases depend on Hsp90 isomerase (PPI) FKBP8, and human butyrate- and its cochaperones Cdc37 and p23 to prevent induced transcript 1 (hB-ind1/HACD3), which their degradation. Hsp90 inhibition resulted in serves as a cochaperone through its p23-like do- the proteasomal degradation of RNA-depend- main (Taguwa et al. 2008, 2009). Both NS5A and ent RNA polymerase of vesicular stomatitis virus polymerase NS5B also depend on cyclophilin (VSV) and rabies virus (RABV) (Connor et al. PPI activity for maturation of their disordered 2007; Xu et al. 2016), HCMV (Basha et al. 2005), domains (Hanoulle et al. 2009; Liu et al. 2009; and RSV (Munday et al. 2015). In contrast, Verdegem et al. 2011). Cyclosporine, a cyclophi- Hsp90 was shown to be required for synthesis, lin inhibitor, suppressed RNA binding by NS5A but not stability or activity, of ﬂock house virus (Nag et al. 2012), and blocked the incorporation (FHV) polymerase (Castorena et al. 2007). In of NS5B into RCs without affecting its protein paramyxoviruses, for example, mumps and levels (Liu et al. 2009). measles (Katoh et al. 2017), Nipah (Bloyet et al. In the reverse-transcribing hepatitis B (HBV) 2016), human parainﬂuenza (HPIV), and SV5 and duck hepatitis B (DHBV) viruses, chaper- (Connor et al. 2007), Hsp90 is only required for ones are required for reverse transcriptase (RT) stabilization of the large polymerase subunit (L) activation. First, Hsp70 and DNAJB1 expose a until it forms a complex with the viral phospho- carboxy-terminal region of the RT, enabling protein. When Hsp90 is inhibited, monomeric L binding to the RNA template (Beck and Nassal is ubiquitinated and targeted for proteasomal 2003; Stahl et al. 2007). This is enough to sup- degradation by E3 ligase carboxyl terminus port in vitro reverse transcription (Beck and Hsp70-interacting protein (CHIP) (Katoh et al. Nassal 2003), but activity is further enhanced 2017). HCV NS5A, an essential part of the viral and maintained by recruitment of Hsp90, p23, RC, is stabilized and recruited to membranes by the Hsp70-Hsp90 organizing protein Hop (Hu a complex consisting of Hsp90, peptidyl-proline and Seeger 1996; Hu et al. 1997, 2002), Cdc37

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(Wang et al. 2002), and Hsp60/HSPD1 (Park ing replication rates, suggesting that accumula- and Jung 2001). Components of the Hsp90 tion of CP serves as an Hsp70-mediated negative complex can remain associated with the poly- feedback loop to limit replication rates (Wang merase, get packaged, and then released from et al. 2018). In the closely related potato virus A, the host cell inside virions (Hu et al. 1997). CP binds to viral RNA and blocks replication; Finally, some viral nonstructural proteins rely phosphorylation by creatine kinase stimulates on the ring-shaped chaperonin TRiC/CCT for CP degradation by Hsp70 and CHIP, allowing their function. TRiC/CCT is recruited to Negri initiation of replication (Lõhmus et al. 2017). bodies, sites of transcription and replication in RABV-infected cells, and knockdown of CCT1 Synthesis, Folding, and Assembly of Viral and CCT3 inhibits RABV replication (Zhang Structural Proteins et al. 2013, 2014). CCT5 was found to mediate TRiC/CCT interactions with nonstructural pro- As mentioned above, chaperones play a key role teins of EBV (Kashuba et al. 1999) and HCV in the folding and assembly of viral capsids and (Inoue et al. 2011). In influenza, polymerase sub- envelopes, the so-called structural proteins that unit PB2 associates with TRiC/CCT as a mono- coat the genome and form the virion. Capsid mer, and silencing of CCT2 resulted in reduced and envelope monomers must assemble into replication, suggesting a function in folding and large regular structures, and often tend to rap- assembly (Fislova et al. 2010). Furthermore, in- idly misfold or oligomerize into insoluble aggre- teraction of HCV F protein with TRiC/CCT co- gates. In influenza, folding intermediates of the chaperone prefoldin interferes with microtubule hemagglutinin glycoprotein are first bound by organization; because HCV replication requires BiP and then transferred to calnexin for contin- microtubule polymerization, F protein may limit ued folding, repair of misfolded intermediates, HCV replication and contribute to viral persis- and prevention of premature oligomerization tence in chronic infection (Tsao et al. 2006). (Singh et al. 1990; Hogue and Nayak 1992; In sum, the complex structure of most viral Tatu et al. 1995). A similar dependence on BiP, polymerases makes them critically dependent and in some cases calnexin/calreticulin, was also on chaperone assistance for folding, assembly, reported for glycoproteins of measles and SV5 and activation, as well as conformational main- (Ng et al. 1989; Roux 1990; Watowich et al. tenance to support continued function. Ac- 1991), VSV and RABV (de Silva et al. 1990, cordingly, chaperone inhibition results in the 1993; Hammond and Helenius 1994), as well misfolding and degradation of many viral poly- as HIV (Earl et al. 1991; Otteken et al. 1996), merases. HCMV (Buchkovich et al. 2008), and rotavirus (Mirazimi and Svensson 2000; Maruri-Avidal et al. 2008). In DENV (Limjindaporn et al. Regulated Transition to Replication 2009; Wati et al. 2009) and HCV (Dubuisson Some RNA viruses regulate the transition be- and Rice 1996; Choukhi et al. 1998; Liberman tween translation, transcription, and replication et al. 1999), BiP, calnexin, and calreticulin levels of their genome in a process that involves Hsp70. are induced; calnexin and calreticulin recognize In RABV, a small regulatory sequence called an early glycosylation intermediate of HCV E1/ leader RNA supports transcription by delaying E2 and recruit PDIA3/ERp57 to catalyze disul- RC formation. Leader RNA function is inhibited fide bridge formation, associating and dissociat- by Hsp70, which is initially down-regulated to ing until the glycoprotein is either properly fold- allow sufficient transcription and later induced ed or degraded (Vieyres et al. 2014). BiP and to shift the balance toward replication (Lahaye calreticulin also interact with misfolded aggre- et al. 2012; Zhang et al. 2017). In beet black gates of E1/E2 and are likely involved in their scorch virus, Hsp70 interacts with viral protein repair (Choukhi et al. 1998). p23 to support RC formation. The viral CP com- Interestingly, BiP also serves as a switch be- petes with p23 for binding to Hsp70 thus reduc- tween the two functions of HBV large envelope

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glycoprotein (L). HBV, which only replicates in tein into a conformation capable of forming the the liver, enters its host cells through interac- nucleocapsid (Knowlton et al. 2018). Further- tions between the preS domain of L and cell more, biogenesis of reovirus σ1 homotrimeric surface heparin sulfate proteoglycans (HSPGs). complex, which mediates binding to host recep- However, HSPGs are found on many cell types, tors, involves cotranslational ATP-independent and so to minimize nonproductive docking out- trimerization of the amino terminus followed by side the liver, HBV particles are released as a sequential binding of Hsp70 and Hsp90/p23, mixed population of both active and inactive which facilitates posttranslational ATP-depen- forms, with preS either exposed or hidden inside dent trimerization of the carboxyl terminus the envelope (Seitz et al. 2016). During transla- (Leone et al. 1996; Gilmore et al. 1998). The im- tion of L, Hsp70 interacts with the preS domain portance of chaperone-mediated assembly for vi- on the cytosolic side of the ER membrane and ral transmission cannot be overemphasized, as actively prevents its translocation while the S misassembled virions will not infect cells and domain is cotranslationally inserted into the may have a dominant negative effect on transmis- membrane (Lambert and Prange 2003). BiP is sion (Geller et al. 2007; Sokolskaja et al. 2010). then responsible for the subsequent posttranslational translocation of the preS domain into the Proteolytic Processing-Competent Folding lumen, which can be inhibited by overexpression of BiP cochaperones such as DNAJB9/ERdj4 or For RNA viruses that synthesize a polyprotein BiP-associated protein (BAP/SIL1) (Awe et al. precursor, proteolytic processing is intimately 2008). Thus, chaperone action mediates a switch linked to protein folding and maturation. Al- between the two functions of preS: virion as- though most viral proteases recognize linear se- sembly in the pretranslocated state or receptor quence elements, chaperone-mediated folding binding in the posttranslocated state (Bruss and of the polyprotein is still required to achieve a Vieluf 1995; Le Seyec et al. 1999). Given that BiP cleavable conformation. In picornaviruses, the was identiﬁed as a liver cell receptor for DENV capsid consists of 60 copies of four subunits that (Jindadamrongwech et al. 2004), it is tempting are generated by cleavage of their precursor P1. to speculate that inactive HBV particles could Hsp70, Hsp90, and p23 associate with newly use cell surface BiP to mature into an HSPG- synthesized P1 but not its cleavage products binding form that supports entry. (Macejak and Sarnow 1992; Geller et al. 2007), While many envelope proteins are clients of and Hsp90 inhibition prevented P1 proteolysis BiP, some capsid proteins are folded and assem- without affecting protease activity, suggesting bled by cytosolic Hsp70 (e.g., polyomavirus, the chaperone complex directs P1 into a prote- SV40, and HCV) (Cripe et al. 1995; Chromy olysis-competent conformation (Fig. 2B; Geller et al. 2003, 2006; Khachatoorian et al. 2014, et al. 2007; Newman et al. 2018). Similarly, 2015, 2016). In HCV, Hsp70 also interacts with Hsp90 and cyclophilin A are required to render DNAJA2/Dj3 and NS5A to support translation HCV polyprotein amenable to cleavage by the through stimulation of the viral IRES (Gonzalez viral protease (Waxman et al. 2001; Kaul et al. et al. 2009). Other DnaJs, however, can have op- 2009). DNAJC14/Hdj3 plays a role in formation posite effects on viral proteins; for example, of yellow fever virus (YFV) RCs by promoting a DNAJA3/hTid1 and DNAJB1/Hdj1 accelerate protease-competent conformation of the viral the degradation of HBV core protein, and their polyprotein, allowing cleavage between non- overexpression or knockdown resulted in de- structural proteins NS3 and 4A (Yi et al. 2012; creased or increased HBV replication, respec- Bozzacco et al. 2016). As such, DNAJC14 is an tively (Sohn et al. 2006). TRiC/CCT, on the important regulator of the ratio between cleaved other hand, facilitates both folding and stabiliza- and uncleaved products, which could drive dif- tion of HBV core (Lingappa et al. 1994) and HIV ferent viral functions. Interestingly, both silenc- Vif (Luo et al. 2016). In reovirus infection, TRiC/ ing and overexpression of DNAJC14 inhibits CCT folds the viral σ3 major outer-capsid pro- replication of multiple ﬂaviviruses, including

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HCV, YFV, and DENV (Yi et al. 2011; Taguwa ptosis by inducing chaperone expression and et al. 2015), suggesting a dose-dependent role in modulating their function in apoptotic signal- maintaining optimal cleavage rates. ing. Early in HIV infection, expression of Hsp70 and Hsp27/HSPB1 is up-regulated and the proteins interact with and suppress Vpr nu- Extracellular Chaperones clear import, thus, preventing premature Vpr- Matureextracellular virus particleswerefoundto induced cell cycle arrest and apoptosis (Iordan- harborcomponentsofthechaperonemachinery. skiy et al. 2004; Liang et al. 2007). Later, expres- Hsp70 was detected in virions of inﬂuenza (Sa- sion of Hsp70 is down-regulated to support viral gara and Kawai 1992), Crimean-Congo hemor- spread through apoptosis (Kumar et al. 2011). In rhagic fever virus (CCHFV) (Surtees et al. 2016), another retrovirus, human T-lymphotropic vi- HIV (Gurer et al. 2002), RABV and VSV (Sagara rus (HTLV), apoptosis is blocked by viral protein and Kawai 1992), and ZIKV (Khachatoorian Tax, which binds and sequesters proapoptotic et al. 2018). HCV was shown to use exosomes DNAJA3/hTid1 in the cytoplasm, preventing for receptor-independent transmission; these its infection-induced relocalization to mito- exosomes contain replication-competent viral chondria (Cheng et al. 2001). HIV and HTLV RNA associated with Ago2, miR-122, and reactivation from latency also requires Hsp90 Hsp90, and their transmission can be suppressed and Cdc37; Hsp90 inhibition in transformed by Hsp90 inhibition. Ago2:miR-122 can support cells destabilized IKK and resulted in apoptosis infection by protecting HCV genomes from 50 (Gao and Harhaj 2013; Anderson et al. 2014). In exonuclease host mRNA decay, whereas Hsp90 EBV, Hsp90 inhibitors both prevented transfor- may stabilize the RISC-loading complex (Bu- mation and induced apoptosis of transformed kong et al. 2014) and possibly mediate rapid re- cells by reducing the amounts of EBNA1, the lease of viral genomes inside the host. Finally, only viral protein expressed during latency extracellular release of chaperones, for example, (Sun et al. 2010). Hsp90 and DNAJB11/ERdj3 Hsp70 can drive type I interferon (IFN)-depen- also promote antiapoptotic signaling in KSHV dent antiviral immunity. Mouse neuronal cells by stabilizing glycoprotein K1 (Wen and Da- infected with measles released Hsp70, which in- mania 2010) and facilitating complex formation ducedIFN-βsignalinginmicroglialcellsthrough between the viral FLIP protein and IKK (Field toll-like receptors 2 and 4 (Kim et al. 2013). et al. 2003), thus, stimulating PI3K/Akt and NF-κB survival signaling, respectively. HCV E2 was shown to block apoptosis and facilitate ANTIAPOPTOTIC SIGNALING persistent infection by inducing the overexpres- Regulated cell death can have either anti- or pro- sion of ER-resident Hsp90 (Grp94/HSP90B1), viral effects, depending on the stage of infection. which can also activate NF-κB. Overexpression It can be detrimental to virus biogenesis early of Grp94/HSP90B1 resulted in increased expres- during infection, but also beneﬁcial for virion sion of antiapoptotic proteins, whereas knock- release and spread at a later stagewhen infectious down abrogated E2-induced prosurvival activity particles have already been formed. Hsp70, (Lee et al. 2008). Interactions of HCV core pro- Hsp90, and Hsp27/HSPB1 are known to regu- tein with either the mitochondrial chaperone late apoptotic signaling. Hsp70 inhibits pro- prohibitin, which is induced during infection, apoptotic Bax activation, cytochrome c release, or Hsp60, led to inhibition of mitochondrial and formation of the apoptosome complex; function, triggered the production of reactive Hsp90 stabilizes and prevents the degradation oxygen species, and enhanced TNF-α-mediated of the prosurvival survivin/BIRC5, PI3K/Akt ki- apoptosis (Kang et al. 2009; Tsutsumi et al. 2009; nase, and NF-κB kinase IKK; and Hsp27/HSPB1 Fujinaga et al. 2011). A similar effect was report- binds and sequesters cytochrome c and caspase- ed for HBV in which Hsp60 colocalized with 3 and activates Akt (Kennedy et al. 2014; Wang HBx protein in the mitochondria and enhanced et al. 2014). Viruses can therefore prevent apo- HBx-induced apoptosis (Tanaka et al. 2004).

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VIRUS-ENCODED CHAPERONE-LIKE tein, suppresses its aggregation, and maintains a PROTEINS conformation that accommodates RNA binding (Majumdar et al. 2004; Yabukarski et al. 2014). Although the vast majority of viruses rely on their ability to induce and compete for host EVOLUTIONARY ASPECTS OF VIRUS– chaperones, some have evolved to encode their CHAPERONE INTERACTIONS own specialized viral chaperones. It is thought that by providing their own chaperones, viruses Viruses are characterized by high mutation can better control and adapt their function and rates, which fuel their evolutionary plasticity improve the recruitment of other host compo- and adaptation to varying environments and nents (Mayer 2005). For example, bacterio- host pressures (Lauring et al. 2013). However, phages have been shown to repurpose the host most mutations destabilize protein folding and GroEL/Hsp60 chaperonin system by encoding a structure (Tokuriki and Tawfik 2009) and may, GroES-like cofactor protein that forms a com- therefore, compromise viral evolution. Chap- plex with host GroEL to promote capsid protein erones, which recognize nonnative protein folding (Ang et al. 2000); others even encode a conformations, can have a significant impact stand-alone chaperonin-like protein required to on organismal fitness as buffers of phenotypic fold a phage protein (Kurochkina et al. 2012; variation. In the event of destabilizing mutations Molugu et al. 2016). Members of the plant clos- leading to misfolding or aggregation, chaper- terovirus family encode Hsp70-like proteins, ones can recognize the misfolded state, suppress which share very little sequence homology aggregation, and either facilitate refolding or with that of their hosts, and are essential for promote protein clearance (Hartl et al. 2011). both virion assembly and microtubule-mediated Therefore, chaperones can improve structural cell-to-cell transmission (Verchot 2012). SV40 and functional plasticity and support expanded large T antigen (TAg) contains an amino-termi- complexity such that is present in numerous vi- nal J-domain that binds Hsp70, stimulates its ral proteins. Genetic and pharmacological per- ATPase activity, and is thought to confer specif- turbations of chaperone function have shed light icity to viral targets (Spence and Pipas 1994; on the possible roles of chaperones in evolution. Wright et al. 2009). HSV also encodes two In bacteria, proteins that depend on chaperonins J-domain proteins: UL14, which is required for for folding evolve faster than chaperonin-inde- the maturation and efficient nuclear transport of pendent proteins through buffering of deleteri- viral protein VP16 and capsid proteins (Ya- ous misfolding-related mutations (Bogumil and mauchi et al. 2002, 2008; Ohta et al. 2011), and Dagan 2010). Endogenous up-regulation or ec- ICP10PK, an Hsp27/HSPB1 homolog that sta- topic overexpression of bacterial chaperonins bilizes Bcl2, up-regulates the expression of can also restore fitness under conditions of in- Hsp70, Hsp27, and Bag1, and enhances the creased mutational load (Fares et al. 2002; Mais- phosphorylation of TGF-β-activated kinase 1 nier-Patin et al. 2005). In contrast, inhibition of (TAK1), leading to activation of the extracellular Hsp90 in Drosophila (Rutherford and Lindquist signal-regulated kinase (ERK) survival pathway 1998) and Arabidopsis (Queitsch et al. 2002) led (Chabaud et al. 2003; Gober et al. 2005; Aurelian to the emergence of detrimental phenotypic var- et al. 2012). Finally, some viruses express pro- iation that was encoded in the genome but teins that show no homology with known chap- masked by chaperone activity. erones, such as the African swine fever virus During viral infection, when adaptation and (ASFV), whose capsid-associated protein 80 survival depend on population diversity, chap- (CAP80) facilitates cotranslational folding of erones are thought to play a fundamental role. the aggregation-prone capsid protein p73 (Cob- The progeny population of highly mutable RNA bold et al. 2001). Similarly, the closely related viruses always consists of an ensemble of closely Nipah and chandipura viruses both encode a related genotypes called “quasispecies,” which phosphoprotein that binds the viral nucleopro- enable survival under constantly changing envi-

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ronmental pressures (Vignuzzi et al. 2006). It is, Hsp90 therefore, likely that acquisition of chaperone dependence allows viral genomes to explore a broader sequence space. This may be particularly beneficial for viral capsid proteins that must consistently mutate surface-exposed epitopes because of immune surveillance pressure. In- Partially deed, a computational analysis of HIV evolution folded showed that mutations related to immune eva- Free energy sion and drug resistance tend to destabilize viral proteins (Olabode et al. 2017). Furthermore, a Native Aggregate fl study of in uenza revealed that a common mu- Conformation space of variants evolved in the tation conferring resistance to a host restriction presence ( ) or absence ( ) of Hsp90 factor loses its fitness benefits when chaperone induction is inhibited at febrile temperatures Figure 3. Role of Hsp90 in shaping poliovirus evolu- (Phillips et al. 2018). These results confirm tion. The low fidelity viral polymerases continuously that viruses use chaperones to uncouple the del- generate sequence variants in the viral population. fi eterious effects of mutations from the benefits of The proteostasis machinery modulates the tness of these sequence variants and thus affects the direction immune evasion. of viral evolution. In poliovirus, Hsp90 modulates the In poliovirus, Hsp90 was recently shown to energy landscape of protein folding and balances facilitate the emergence of sequence variants trade-offs between protein stability and aggregation with increased hydrophobicity, potentially lead- for the capsid protein variants. By protecting against ing to both higher stability and aggregation pro- aggregation, Hsp90 allows the emergence of more pensity (Fig. 3). As such, Hsp90 mediates the stable variants because their higher hydrophobic trade-off between stability and aggregation by character has the drawback of increased aggregation propensity. maintaining solubility of these variants. Inhibi- tion of Hsp90 was not only associated with accumulation of variants that reduced aggregation ing that chaperones can increase the fitness cost at the expense of stability, it also promoted local of specific mutations (Phillips et al. 2017). These codon deoptimization, leading to slower trans- experiments indicate that chaperones profound- lation and allowing more time for either chap- ly affect viral evolution and adaptation by mod- erone-independent or chaperone-mediated co- ulating trade-offs between protein stability and translational folding. In HCV, inhibition of aggregation as well as translation rate and co- cyclophilin A, which is thought to function cotranslational processing (Geller et al. 2018). translationally, was associated with emergence of mutations that slow down the kinetics of CHAPERONES AS BROAD-SPECTRIUM polyprotein processing (Kaul et al. 2009). An- ANTIVIRAL TARGETS other study showed that fixation of nonsynon- ymous mutations in influenza was slower with Viral infections are a major cause of human Hsp90 inhibition and faster with elevated chap- morbidity and mortality, imposing a heavy eco- erone activity induced by HSF1 activation. Al- nomic burden worldwide. Despite major efforts, though moderately destabilizing mutations in only a handful of antivirals are currently avail- the polymerase were tolerated regardless of the able, largely because of the rapid acquisition of proteostatic intervention, strongly destabilizing resistance to drugs directed against viral en- mutations were only observed when chaperone zymes. Any drug targeting a protein that is levels were induced by HSF1 activation. Inter- under the replicative control of a virus may be estingly, some polymerase mutations rendered rendered ineffective through mutations that the virus significantly more fit with Hsp90 inhi- easily and frequently generate escape mutants. bition and less fit with HSF1 activation, suggest- Therefore, targeting host factors involved in

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proteostasis may be an attractive alternative, giv- 2009; Weng et al. 2012; Langsjoen et al. 2017). en their widespread requirement for the replica- Cyclophilin inhibitors, including cyclosporine tion of many, if not most, viruses. The unique and its nonimmunosuppressive derivatives, in- constraints on chaperone-mediated folding in hibit HCV infection both in tissue cultures and infected cells could render viruses hypersensi- animals by blocking the interaction between tive to inhibitors of these chaperones with rela- NS5A and viral RNA (Nag et al. 2012). Similar- tively low toxicity to the host. Because numerous ly, cyclosporine blocks the incorporation of HIV viruses rely on various chaperones, as described envelope protein into virions (Sokolskaja et al. above, such inhibitors have the potential to be- 2010), and its therapeutic potential is currently come broad-spectrum antivirals. being evaluated in clinical trials (Nicolas et al. Both Hsp90 and Hsp70 are highly druggable, 2017). Direct and indirect PDI inhibitors can with multiple structurally diverse inhibitors also inhibit folding and assembly of the envelope identified to date showing therapeutic potential proteins of CHIKV and ZIKV (Langsjoen et al. in cancer and other pathologies (Neckers and 2017). The inability of viruses to elicit resistance Workman 2012; Kumar et al. 2016). As of 2017, to drugs targeting chaperones, together with several Hsp90 and Hsp70 inhibitors were being their favorable therapeutic window, low toxicity, evaluated in clinical trials, but a first-in-class and efficacy against broad families of related vi- drug has yet to be approved (Chatterjee and ruses provide hope that these types of com- Burns 2017). Small molecule Hsp90 inhibitors pounds could be used both therapeutically and geldanamycin (GA) and 17-AAG show antiviral prophylactically against acute viral infections activity in tissue cultures against a diverse range and emerging epidemics. of viruses, including herpesviruses (HSV, KSHV, andEBV),arboviruses(HCV,chikungunyavirus CONCLUDING REMARKS [CHIKV]), retrotranscribing viruses (HBV and HIV) and influenza, and in animals against po- Essentially, all steps of the viral replication cycle liovirus and HCV (reviewed in Geller et al. 2012; depend on interactions between chaperones and Wang et al. 2017). In the case of poliovirus, de- viral proteins. Studying the intricacies of viral velopment of drug resistance was observed for proteostasis continues to illuminate basic prin- most antivirals tested but never for Hsp90 inhib- ciples of chaperone function in both healthy itors (Geller et al. 2007). Allosteric Hsp70 inhib- and infected cells, and may lead to novel types itors,suchasJG40andHS-72,werealsoshownto of resistance-free antiviral drugs. Considering potently block infection with flaviviruses, for ex- their panviral activity, involvement in multiple ample, DENV, YFV, and JEV in tissue cultures, steps throughout the viral life cycle, favorable without host toxicity or emergence of drug resis- safety and tolerability profiles, and lack of ob- tance. While HS-72 was found to inhibit DENV served drug resistance, chaperone inhibitors entry through disruption of Hsp70 association could become a valuable tool in our fight against with the DENV receptor complex (Howe et al. the global burden of viral infection. 2016), JG40 was found to affect multiple steps of the virus life cycle, including entry, replication, ACKNOWLEDGMENTS and assembly (Taguwa et al. 2015). JG40 also suppressed the production of proinflammatory R.A. is supported by a Human Frontier Science cytokines and chemokines, which contribute to Program long-term fellowship. J.F. is supported the pathology of some viral infections. by NIAID Grant AI127447 and a grant from Members of the oxidative folding pathway, DARPA. PPIs (cyclophilins), and protein disulfide isom- erases (PDIs) have also been implicated in mul- REFERENCES tiple steps of the flavivirus life cycle, including Agostini I, Popov S, Li J, Dubrovsky L, Hao T, Bukrinsky M. RC formation, polyprotein processing, envelope 2000. Heat-shock protein 70 can replace viral protein R of protein folding, and virion assembly (Kaul et al. HIV-1 during nuclear import of the viral preintegration

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R. Aviner and J. Frydman

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Proteostasis in Viral Infection: Unfolding the Complex Virus− Chaperone Interplay

Ranen Aviner and Judith Frydman

Cold Spring Harb Perspect Biol published online March 11, 2019

Subject Collection Protein Homeostasis

Proteome-Scale Mapping of Perturbed The Amyloid Phenomenon and Its Significance in Proteostasis in Living Cells Biology and Medicine Isabel Lam, Erinc Hallacli and Vikram Khurana Christopher M. Dobson, Tuomas P.J. Knowles and Michele Vendruscolo Pharmacologic Approaches for Adapting A Chemical Biology Approach to the Chaperome Proteostasis in the Secretory Pathway to in Cancer−−HSP90 and Beyond Ameliorate Protein Conformational Diseases Tony Taldone, Tai Wang, Anna Rodina, et al. Jeffery W. Kelly Cell-Nonautonomous Regulation of Proteostasis Proteostasis in Viral Infection: Unfolding the in Aging and Disease Complex Virus−Chaperone Interplay Richard I. Morimoto Ranen Aviner and Judith Frydman The Autophagy Lysosomal Pathway and The Proteasome and Its Network: Engineering for Neurodegeneration Adaptability Steven Finkbeiner Daniel Finley and Miguel A. Prado Functional Modules of the Proteostasis Network Functional Amyloids Gopal G. Jayaraj, Mark S. Hipp and F. Ulrich Hartl Daniel Otzen and Roland Riek Protein Solubility Predictions Using the CamSol Chaperone Interactions at the Ribosome Method in the Study of Protein Homeostasis Elke Deuerling, Martin Gamerdinger and Stefan G. Pietro Sormanni and Michele Vendruscolo Kreft Recognition and Degradation of Mislocalized Mechanisms of Small Heat Shock Proteins Proteins in Health and Disease Maria K. Janowska, Hannah E.R. Baughman, Ramanujan S. Hegde and Eszter Zavodszky Christopher N. Woods, et al. The Nuclear and DNA-Associated Molecular Structure, Function, and Regulation of the Hsp90 Chaperone Network Machinery Zlata Gvozdenov, Janhavi Kolhe and Brian C. Maximilian M. Biebl and Johannes Buchner Freeman

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