Biology

Dr. Parikshit Bagchi
University of Michigan Medical School, Ann Arbor, USA

To infect cells, the non-enveloped polyomavirus SV40 traffics from the cell surface to the endoplasmic reticulum (ER) where it penetrates the ER membrane to reach cytosol. In the cytosol, the virus moves further into the nucleus to stimulate lytic infection or cell transformation. ER-to-cytosol membrane transport of SV40, a critical infection step, remains unclear. It is previously reported that SV40 is partially destabilized in the ER lumen, generating a hydrophobic viral particle that integrates into the ER membrane in preparation for extraction into the cytosol. Several ER membrane proteins including three structurally homologous ER membrane bound DnaJ proteins (B12, B14, C18) support this membrane penetration step. But as we found that these three J proteins perform non-overlapping role in SV40 membrane penetration step, we tried to check their binding partners through an unbiased IP-mass spec study. As a preferential binding partner of C18, we now find that a multi-subunit ER membrane complex called the ER membrane protein complex or EMC supports SV40 infection by stabilizing SV40 within the ER membrane. Transmembrane region of largest subunit of the complex, EMC1, binds to SV40 coat proteins and stabilizes the membrane penetrating virus. This EMC1-dependent stabilization prevents premature viral destabilization, enabling a cytosolic chaperone complex to properly engage and extract the virus into the cytosol to complete the membrane penetration event. These findings are consistent with the normal cellular function of the EMC1, which is thought to stabilize multi-pass membrane proteins during their biogenesis. Our results illuminate how SV40 exploits an ER quality control machinery during infection, specifically revealing a novel principle in which coordinated destabilization and stabilization of a non-enveloped virus is crucial to its membrane penetration process.