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Review
. 2021 May 21;13(6):958.
doi: 10.3390/v13060958.

How DNA and RNA Viruses Exploit Host Chaperones to Promote Infection

Kaitlyn Speckhart  1   2 , Jeffrey M Williams  1 , Billy Tsai  1   2
Affiliations
Review

How DNA and RNA Viruses Exploit Host Chaperones to Promote Infection

Kaitlyn Speckhart et al. Viruses. .

Abstract

To initiate infection, a virus enters a host cell typically via receptor-dependent endocytosis. It then penetrates a subcellular membrane, reaching a destination that supports transcription, translation, and replication of the viral genome. These steps lead to assembly and morphogenesis of the new viral progeny. The mature virus finally exits the host cell to begin the next infection cycle. Strikingly, viruses hijack host molecular chaperones to accomplish these distinct entry steps. Here we highlight how DNA viruses, including polyomavirus and the human papillomavirus, exploit soluble and membrane-associated chaperones to enter a cell, penetrating and escaping an intracellular membrane en route for infection. We also describe the mechanism by which RNA viruses-including flavivirus and coronavirus-co-opt cytosolic and organelle-selective chaperones to promote viral endocytosis, protein biosynthesis, replication, and assembly. These examples underscore the importance of host chaperones during virus infection, potentially revealing novel antiviral strategies to combat virus-induced diseases.

Keywords: Golgi; chaperones; coronavirus; endoplasmic reticulum; flavivirus; human papillomavirus; infection; polyomavirus SV40; viruses.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Exploiting ER and cytosolic chaperones during ER escape and disassembly of polyomavirus SV40. (A) Polyomavirus SV40 entry pathway. During entry, SV40 undergoes receptor-mediated endocytosis, trafficking to the endosome and then the ER. Here it penetrates the ER membrane to reach the cytosol and then the nucleus to cause infection. (B) In the ER, PDI family proteins (PDI, ERp57, and ERdj5) reduce and isomerize the SV40 disulfide bonds (step 1), while another PDI family member (ERp29) unfolds the VP1 C-terminal arm—these reactions disrupt the viral architecture that exposes the SV40 hydrophobic VP2 and VP3 proteins. As a consequence, a hydrophobic SV40 particle is formed which integrates into the ER membrane (step 2). SV40 then reorganizes the ER membrane to construct an exit site (called foci) where the virus crosses to reach the cytosol. During foci formation, SV40 directs the ER membrane protein EMC1 to relocate to the foci where it stabilizes the membrane-inserted SV40 (step 3). SV40 further triggers DNA J protein family members (B12, B14, and C18) to accumulate in the foci—this recruits a cytosol-localized chaperone extraction machinery (Hsc70, Hsp105, Bag2, and SGTA) that propels SV40 into the cytosol (step 4). The dynein motor adaptor BICD disassembles the cytosol-localized virus (step 5), forming a subviral particle that enters the nucleus to trigger infection.
Figure 2
Figure 2
Co-opting soluble and transmembrane chaperones during internalization, disassembly, and endosomal membrane insertion of human papillomavirus. (A) HPV entry pathway. During entry, HPV undergoes receptor-dependent endocytosis, transporting to the endosome and then the Golgi. HPV then buds from the Golgi during mitosis, entering the nucleus after nuclear membrane breakdown to cause infection. (B) At the plasma membrane, the peptidyl-prolyl isomerase activity of cyclophilins (CyP) induces conformational changes in the viral capsid proteins that expose a furin cleavage site at the N-terminus of L2 (step 1). After furin cleavage, the virus is transferred to the tetraspanin-enriched microdomain (TEM) and endocytosed. In the endosome, cyclophilins mediate partial dissociation of L1 from L2 and the viral genome (step 2), further exposing L2. Additionally, in the endosome, the transmembrane protein γ-secretase interacts with L2 and acts as a chaperone to promote the insertion of the L2 C-terminus across the endosomal membrane (step 3). The cytosol-exposed L2 recruits host sorting factors, which traffic the virus to the Golgi en route for infection.
Figure 3
Figure 3
Hijacking cytosolic and ER-localized chaperones to promote flavivirus infection. Flavivirus DENV entry pathway (see text for more details). Hsp70 chaperone, in concert with J proteins, facilitate virus endocytosis, protein biosynthesis, and assembly. Hsp70 is proposed to mediate endocytosis of the incoming DENV particle (step 1, orange circle), but how this is accomplished remains unclear. In contrast, Hsp70 binds directly to the NS5 RNA polymerase in order to promote biosynthesis and function of this enzyme (step 3, orange circle), thereby indirectly facilitating viral replication (step 4, orange circle). Hsp70 also interacts with and stabilizes the C protein to support viral assembly (step 5, orange circle). In addition to cytosolic Hsp70, the ER membrane protein complex EMC likewise contributes to DENV infection by assisting in biosynthesis of the nonstructural membrane proteins NS4A and NS4B (step 3, green circle). Since NS4A and NS4B are important for formation of the virus replication compartment (step 4, green circle), EMC thus supports virus replication indirectly.
Figure 4
Figure 4
Repurposing ER-associated chaperones during coronavirus entry. Coronavirus CoV entry pathway (see text for more details). Initial attachment to the plasma membrane and subsequent receptor binding to the viral particle at the cell surface is facilitated by the ER luminal BiP chaperone (step 1). The virus then undergoes endocytosis to reach the endosome (step 2). Here fusion between the viral and endosomal membranes results in release of the viral genome into the cytosol. The cytosol-localized genomic RNA is then cotranslationally translocated on the ER membrane (step 3), generating the viral PP1a and PP1ab polypeptides (step 4); in this step, the ER-resident chaperones BiP and GRP94 are thought to facilitate proper protein folding. The polyproteins are proteolytically cleaved, forming NSP1-16. Some of these nonstructural proteins (NSPs) assist in formation of the double-membrane vesicle (DMV). Within the DMV, the replicase and transcriptase complex (RTC) is formed (step 5). At this site, viral genome replication occurs, producing many copies of the full-length RNA genome. Additionally, subgenomic RNAs are generated via nested transcription. The full-length and subgenomic RNAs are released from the DMV (step 6). Those subgenomic RNAs encoding M, S, and E are delivered to the ER where these structural proteins are synthesized (step 7); in this process, the ER luminal calnexin chaperone assists in proper folding of the viral proteins. By contrast, the subgenomic RNA encoding N is translated in the cytosol to form the N protein which complexes with the newly-synthesized viral full-length genomic RNA. The M, S, and E structural proteins exit the ER and transport to the ERGIC for packaging with the N protein-genomic RNA complex (step 8). Finally, the mature viral particle is formed and trafficked along the secretory pathway for secretion (step 9).
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