Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Proteostasis in Viral Infection: Unfolding the Complex Virus–Chaperone Interplay 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 mul- tifunctional, 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 chaper- one 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; Editors: Richard I. Morimoto, F. Ulrich Hartl, and Jeffery W. Kelly Additional Perspectives on Protein Homeostasis available at www.cshperspectives.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a034090 1 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press 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 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a034090 Downloaded from http://cshperspectives.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press 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