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

Abstract

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.

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.

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.

Figure 3.

Role of Hsp90 in shaping poliovirus evolution. The low fidelity viral polymerases continuously generate sequence variants in the viral population. The proteostasis machinery modulates the fitness of these sequence variants and thus affects the direction of viral evolution. In poliovirus, Hsp90 modulates the energy landscape of protein folding and balances trade-offs between protein stability and aggregation for the capsid protein variants. By protecting against aggregation, Hsp90 allows the emergence of more stable variants because their higher hydrophobic character has the drawback of increased aggregation propensity.