Regulated Erlin-dependent release of the B12 transmembrane J-protein promotes ER membrane penetration of a non-enveloped virus

The molecular mechanism by which non-enveloped viruses penetrate biological membranes remains enigmatic. The non-enveloped polyomavirus SV40 penetrates the endoplasmic reticulum (ER) membrane to reach the cytosol and cause infection. We previously demonstrated that SV40 creates its own membrane penetration structure by mobilizing select transmembrane proteins to distinct puncta in the ER membrane called foci that likely function as the cytosol entry sites. How these ER membrane proteins reorganize into the foci is unknown. B12 is a transmembrane J-protein that mobilizes into the foci to promote cytosol entry of SV40. Here we identify two closely related ER membrane proteins Erlin1 and Erlin2 (Erlin1/2) as B12-interaction partners. Strikingly, SV40 recruits B12 to the foci by inducing release of this J-protein from Erlin1/2. Our data thus reveal how a non-enveloped virus promotes its own membrane translocation by triggering the release and recruitment of a critical transport factor to the membrane penetration site.