A PDI Family Network Acts Distinctly and Coordinately with ERp29 To Facilitate Polyomavirus Infection

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.

PROTEIN DISULFIDE ISOMERASE LIKE 5-1is a susceptibility factor to plant viruses

“…Knockdown of specific PDI members could influence the infectivity of several viruses, e.g., HIV, Newcastle disease virus (NDV) and mouse polyomavirus (31,32,35). In human cell cultures, knockdown of the PDI family members, PDI, ERp29, ERp57, and ERp72 inhibited the accumulation of viral particles (30,34,36). Our data support and extend the role of PDIs as important host components required for the successful infection or replication of viruses in animals to plants.…”

“…The situation is different in animals. PDI family members, particularly cellsurface PDI proteins, may participate in the infection process of multiple human and animal viruses, e.g., HIV (HIV) (30)(31)(32)(33)(34)(35)(36). Nonspecific inhibition of PDI activity suppressed the PDI-mediated redox environment of plasma membranes (33) and therefore interfered with HIV envelope protein-directed cell fusions (32).…”

Both platelet- and endothelial cell–derived ERp5 support thrombus formation in a laser-induced mouse model of thrombosis

“…This study demonstrated that 3 thiol isomerases coordinately catalyze the unfolding of C-terminal arm of VP1, the major coat protein of the virus, to facilitate infection. 39 Alternatively or additionally, each of these thiol isomerases may interact with a unique set of substrates. The b 3 integrins may facilitate the roles of ERp5, ERp57, and PDI in thrombus formation by providing a platform for formation of complexes with these enzymes and their thrombosis-relevant substrates on the surface of activated platelets or endothelial cells at sites of vascular injury.…”

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

“…Several studies pinpointed select ER protein quality control components responsible for inducing conformational changes to the virus. Specifically, members of the protein disulfide isomerase (PDI) family use either their oxidoreductase or chaperone activities to disrupt the forces that stabilize the VP1 pentamers (14)(15)(16)(17)(18). These reactions expose the minor coat proteins VP2/3, generating a hydrophobic viral particle that binds to and integrates into the ER membrane (16,(19)(20)(21)(22)(23); viral integration with the ER membrane thereby initiates the membrane penetration process.…”