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Review
. 2016 Aug 29;8(9):242.
doi: 10.3390/v8090242.

How Polyomaviruses Exploit the ERAD Machinery to Cause Infection

Allison Dupzyk  1 , Billy Tsai  2
Affiliations
Review

How Polyomaviruses Exploit the ERAD Machinery to Cause Infection

Allison Dupzyk et al. Viruses. .

Abstract

To infect cells, polyomavirus (PyV) traffics from the cell surface to the endoplasmic reticulum (ER) where it hijacks elements of the ER-associated degradation (ERAD) machinery to penetrate the ER membrane and reach the cytosol. From the cytosol, the virus transports to the nucleus, enabling transcription and replication of the viral genome that leads to lytic infection or cellular transformation. How PyV exploits the ERAD machinery to cross the ER membrane and access the cytosol, a decisive infection step, remains enigmatic. However, recent studies have slowly unraveled many aspects of this process. These emerging insights should advance our efforts to develop more effective therapies against PyV-induced human diseases.

Keywords: ERAD; SV40; membrane penetration; polyomavirus; protein aggregation.

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Conflict of interest statement

This work is funded by the National Institutes of Health (RO1 AI064296-10 and RO1 GM113722). None of the authors have a conflict of interest.

Figures

Figure 1
Figure 1
Simian virus 40 (SV40) structure and entry pathway. (A) SV40 consists of 360 VP1 copies arranged as 72 pentamers, which are localized on the viral surface. The pentamers are stabilized by disulfide bonds, as well as by interactions between the VP1 carboxy-terminus, which invades a neighboring pentamer (black curved lines). VP1 also binds to the underlying internal hydrophobic proteins VP2 and VP3. (B) To infect cells, SV40 interacts with the glycolipid receptor ganglioside GM1 on the plasma membrane, internalizes, and traffics to the endolysosomes (step 1). The virus then targets to the endoplasmic reticulum (ER) using a lipid-sorting mechanism (step 2), from where it crosses the ER membrane to access the cytosol (step 3). Upon entering the cytosol, SV40 mobilizes into the nucleus (step 4), where ensuing transcription and replication of the viral genome causes lytic infection or cellular transformation. NPC: nuclear pore complex.
Figure 2
Figure 2
ER-associated degradation (ERAD) pathway. ERAD is an ER quality control pathway that identifies and triages misfolded ER proteins. In the first step, a misfolded protein is recognized by ER-resident chaperones, which target the misfolded client to the retro-translocation machinery on the ER membrane (step 1). Next the misfolded client is retro-translocated across the ER membrane by crossing the retro-translocation channel (step 2); a major component of this channel is the Sel1L-Hrd1 membrane complex. When the client emerges into the cytosol, it is ubiquitinated by the catalytic domain of Hrd1 that faces the cytosol, eventually resulting in polyubiquitinaton of the substrate (step 3). In the final step, the client is extracted into the cytosol by p97 (and its cofactors), and delivered to the proteasome for degradation (step 4). Sel1L: protein sel-1 homolog 1; Hrd1: E3 ubiquitin-protein ligase synoviolin; Poly(Ub)n: polyubiquitin chain; RING: Really Interesting New Gene finger domain.
Figure 3
Figure 3
ER-to-cytosol membrane penetration of SV40. Penetration across the ER membrane to reach the cytosol is a decisive SV40 infection step. This process can be conceptually divided into ER lumenal, membrane, and cytosolic events. (A) During ER lumenal events, protein disulfide isomerase (PDI) family members impart conformational changes to SV40, generating a hydrophobic viral particle by exposing its VP2 and VP3 hydrophobic proteins (step 1). This hydrophobic virus is maintained in a soluble state by interacting with ADP-binding immunoglobulin protein (BiP), which is formed by the action of the J-protein ERdj3 (step 2). When the SV40-BiP complex is proximal to the ER membrane, the nucleotide exchange factor glucose-regulated protein 170 kDa (Grp170) induces nucleotide exchange of BiP, generating ATP-BiP that releases SV40 (step 3). The hydrophobic SV40 in turn binds to and integrates into the ER membrane to initiate membrane transport. (B) During ER membrane events, the membrane-embedded SV40 binds to the B-cell receptor-associated protein 31 (BAP31) membrane protein (step 1), a step thought to stabilize the viral structural integrity. Concomitant with this step, SV40 also induces the lateral reorganization of different ER membrane proteins (including BAP31 and the J-proteins B12, B14, and C18) to form discrete puncta called foci (step 2)—the foci structures are believed to represent the cytosol entry sites. How this virus induces foci formation is not entirely understood. (C) During the cytosolic events, the J-proteins B12/B14/C18 recruit a cytosolic complex composed of 70 kDa heat shock protein (Hsc70), human heat shock protein 105 kDa (Hsp105), and small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA) that extracts SV40 into the cytosol. The J-proteins first convert Hsc70 to ADP-Hsc70, allowing this chaperone to bind to SV40. The nucleotide exchange factor Hsp105 changes ADP-Hsc70 to ATP-Hsc70, which releases SV40 from Hsc70. Because Hsp105 is also a bonafide chaperone, it captures SV40 once the virus is released from Hsc70. Iterative cycles of Hsc70-Hsp105 binding to and release from SV40 is thought to extract SV40 into the cytosol. Hsp105 can also disassemble the virus, a reaction that may be coupled to the extraction process. SGTA’s precise function is unclear, but can either regulate Hsc70’s ability to engage SV40, bring Hsc70 and Hsp105 in proximity due to its ability to dimerize, or catalyze an event post ER membrane penetration such as in facilitating cytosol-to-nucleus transport. SH: hydrosulfide radical.
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