Limits...
How Polyomaviruses Exploit the ERAD Machinery to Cause Infection

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5035956&req=5

viruses-08-00242-f003: 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.

Mentions: After trafficking to the ER, SV40 is thought to disguise as a “misfolded” substrate, co-opting components of the ERAD machinery in order to penetrate the ER membrane and reach the cytosol. To do so, it first undergoes conformational changes that partially uncoat the virus. This conformational change generates a hydrophobic viral particle that binds to and inserts into the ER membrane, a step required for successful membrane transport. Multiple PDI family members impart SV40 structural alterations in the ER, including PDI, ERp57, and ERdj5 (Figure 3A, step 1; [50,51,52]); there is evidence that ERdj5 also executes an important role during BK PyV infection [52]. In the case of the murine PyV, another PDI family member called ERp29 was found to locally unfold the VP1 carboxy-terminal arm [53,54], a reaction that in conjunction with PDI and ERp57 [51,55] generates a hydrophobic virus by exposing the internal hydrophobic proteins VP2 and VP3 [56,57]. Of note, the PDI-ERp57-ERp29 triad has also been reported to act on JC PyV during infection [58].


How Polyomaviruses Exploit the ERAD Machinery to Cause Infection
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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035956&req=5

viruses-08-00242-f003: 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.
Mentions: After trafficking to the ER, SV40 is thought to disguise as a “misfolded” substrate, co-opting components of the ERAD machinery in order to penetrate the ER membrane and reach the cytosol. To do so, it first undergoes conformational changes that partially uncoat the virus. This conformational change generates a hydrophobic viral particle that binds to and inserts into the ER membrane, a step required for successful membrane transport. Multiple PDI family members impart SV40 structural alterations in the ER, including PDI, ERp57, and ERdj5 (Figure 3A, step 1; [50,51,52]); there is evidence that ERdj5 also executes an important role during BK PyV infection [52]. In the case of the murine PyV, another PDI family member called ERp29 was found to locally unfold the VP1 carboxy-terminal arm [53,54], a reaction that in conjunction with PDI and ERp57 [51,55] generates a hydrophobic virus by exposing the internal hydrophobic proteins VP2 and VP3 [56,57]. Of note, the PDI-ERp57-ERp29 triad has also been reported to act on JC PyV during infection [58].

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus