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.
Polyomavirus (PyV) is a DNA tumor virus known to cause many debilitating and devastating human diseases, ranging from neurological disorders and kidney diseases to cancer. A crucial step in its infection pathway is penetration of the viral particle across the membrane of a sub-cellular compartment known as the endoplasmic reticulum (ER). However, the molecular mechanism by which PyV breaches the ER membrane remains largely mysterious. In this proposal, we intend to clarify this enigmatic process.
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