How polyomaviruses penetrate the ER membrane

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Abstract This application's goal is to probe how the non-enveloped polyomavirus (PyV) hijacks a novel endoplasmic reticulum (ER) membrane protein complex called the EMC to promote its ER-to-cytosol membrane penetration, a decisive infection step. To cause infection, PyV undergoes receptor-mediated endocytosis, trafficking from the plasma membrane to the ER where it subsequently penetrates the ER membrane to reach the cytosol. From the cytosol, the virus mobilizes into the nucleus where transcription and replication of the viral genome ensue, leading to lytic infection or cellular transformation. While my laboratory and others have provided significant insights into ER luminal and cytosolic events that drive PyV ER-to-cytosol membrane transport, what remains a major gap in our understanding are events in the ER lipid bilayer that link the luminal and cytosolic reactions. Accordingly, this proposal's objective is to clarify how the ER membrane protein complex EMC facilitates PyV ER membrane penetration by potentially coupling reactions in the ER lumen and in the cytosol.