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A PDI family network acts distinctly and coordinately with ERp29 to facilitate polyomavirus infection
Christopher P Walczak1, Billy Tsai
1Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Abstract:
Endoplasmic reticulum (ER)-to-cytosol membrane transport is a decisive infection step for the murine polyomavirus (Py). We previously determined that ERp29, a protein disulfide isomerase (PDI) member, extrudes the Py VP1 C-terminal arm to initiate ER membrane penetration. This reaction requires disruption of Py's disulfide bonds. Here, we found that the PDI family members ERp57, PDI, and ERp72 facilitate virus infection. However, while all three proteins disrupt Py's disulfide bonds in vitro, only ERp57 and PDI operate in concert with ERp29 to unfold the VP1 C-terminal arm. An alkylated Py cannot stimulate infection, implying a pivotal role of viral free cysteines during infection. Consistent with this, we found that although PDI and ERp72 reduce Py, ERp57 principally isomerizes the virus in vitro, a reaction that requires viral free cysteines. Our mutagenesis study subsequently identified VP1 C11 and C15 as important for infection, suggesting a role for these residues during isomerization. C11 and C15 also act together to stabilize interpentamer interactions for a subset of the virus pentamers, likely because some of these residues form interpentamer disulfide bonds. This study reveals how a PDI family functions coordinately and distinctly to promote Py infection and pinpoints a role of viral cysteines in this process.
Insights
Protein disulfide isomerases (PDIs) like ERp57 and PDI assist murine polyomavirus (Py) infection by disrupting viral disulfide bonds and unfolding viral proteins, highlighting the importance of viral cysteines.
Area of Science:
- Virology
- Molecular Biology
- Cell Biology
Background:
- Endoplasmic reticulum (ER)-to-cytosol transport is crucial for murine polyomavirus (Py) infection.
- ERp29, a protein disulfide isomerase (PDI), initiates ER membrane penetration by extruding the Py VP1 C-terminal arm, requiring disulfide bond disruption.
Purpose of the Study:
- To investigate the roles of other PDI family members (ERp57, PDI, ERp72) in Py infection.
- To elucidate the specific mechanisms by which PDIs facilitate viral entry and the importance of viral cysteines.
Main Methods:
- In vitro assays to assess PDI disruption of Py disulfide bonds.
- Analysis of PDI cooperation with ERp29 in unfolding the VP1 C-terminal arm.
- Mutagenesis studies to identify critical viral cysteine residues (C11, C15) in VP1.
Main Results:
- ERp57, PDI, and ERp72 were found to facilitate Py infection.
- ERp57 and PDI, but not ERp72, cooperate with ERp29 to unfold the VP1 C-terminal arm.
- Viral cysteines C11 and C15 are essential for infection, involved in isomerization and stabilizing interpentamer interactions.
Conclusions:
- The PDI family exhibits distinct yet coordinated functions in promoting Py infection.
- Viral free cysteines play a pivotal role in Py infection, particularly during PDI-mediated isomerization.
- Specific viral cysteines (C11, C15) are critical for both viral entry and structural integrity.
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