Biological membranes represent a major barrier during virus infection. While the mechanism by which an enveloped virus breaches the limiting membrane of a host cell is well-characterized, this membrane penetration process is poorly understood for non-enveloped viruses. Indeed, most available insights on membrane transport of non-enveloped viruses are built upon in vitro studies.
A new paper describes a cell-based assay to explain the molecular mechanism by which the non-enveloped SV40 penetrates the endoplasmic reticulum (ER) membrane to access the cytosol, a critical step in infection. Strikingly, it shows that SV40 breaches the ER membrane as a large and intact virus particle, despite the conformational changes it experiences in the ER lumen. This suggests that the ER membrane can accommodate translocation of a large protein complex, possibly through either a sizeable protein channel or the ER membrane bilayer. This data illuminates the cellular mechanism by which a non-enveloped virus penetrates the limiting membrane of a target cell during infection.
A Large and Intact Viral Particle Penetrates the Endoplasmic Reticulum Membrane to Reach the Cytosol. 2011 PLoS Pathog 7(5): e1002037. doi:10.1371/journal.ppat.1002037
Non-enveloped viruses penetrate host membranes to infect cells. A cell-based assay was used to probe the endoplasmic reticulum (ER)-to-cytosol membrane transport of the non-enveloped SV40. We found that, upon ER arrival, SV40 is released into the lumen and undergoes sequential disulfide bond disruptions to reach the cytosol. However, despite these ER-dependent conformational changes, SV40 crosses the ER membrane as a large and intact particle consisting of the VP1 coat, the internal components VP2, VP3, and the genome. This large particle subsequently disassembles in the cytosol. Mutant virus and inhibitor studies demonstrate VP3 and likely the viral genome, as well as cellular proteasome, control ER-to-cytosol transport. Our results identify the sequence of events, as well as virus and host components, that regulate ER membrane penetration. They also suggest that the ER membrane supports passage of a large particle, potentially through either a sizeable protein-conducting channel or the lipid bilayer.