This application aims to elucidate the molecular mechanism by which the two non-enveloped viruses polyomavirus (Py) and SV40 penetrate the endoplasmic reticulum (ER) membrane. To infect cells, Py and SV40 bind to glycolipid receptors called gangliosides on the host cell surface and are internalized. The viruses are then transported to the lumen of the ER where they co-opt host cell machineries to cross the ER membrane and reach the cytosol. From the cytosol, Py and SV40 are transported into the nucleus where transcription and replication of the viral DNA ensue, leading to lytic infection or cell transformation. How these viruses penetrate the ER membrane to reach the cytosol, a decisive infection event, remains mysterious and is a process we intend to clarify in this proposal.
The murine polyomavirus (Py) and SV40 are tumor-causing viruses. A decisive step in their infection pathway is transport of the viruses across the membrane of a sub-cellular compartment known as the endoplasmic reticulum (ER). However, the molecular basis by which Py and SV40 breach the ER membrane remains enigmatic. In this proposal, we intend to elucidate this mysterious process.
|Walczak, Christopher Paul; Ravindran, Madhu Sudhan; Inoue, Takamasa et al. (2014) A cytosolic chaperone complexes with dynamic membrane J-proteins and mobilizes a nonenveloped virus out of the endoplasmic reticulum. PLoS Pathog 10:e1004007|
|Inoue, Takamasa; Tsai, Billy (2013) How viruses use the endoplasmic reticulum for entry, replication, and assembly. Cold Spring Harb Perspect Biol 5:a013250|
|Inoue, Takamasa; Tsai, Billy (2011) A large and intact viral particle penetrates the endoplasmic reticulum membrane to reach the cytosol. PLoS Pathog 7:e1002037|
|Qian, Mengding; Tsai, Billy (2010) Lipids and proteins act in opposing manners to regulate polyomavirus infection. J Virol 84:9840-52|
|Rainey-Barger, Emily K; Mkrtchian, Souren; Tsai, Billy (2009) The C-terminal domain of ERp29 mediates polyomavirus binding, unfolding, and infection. J Virol 83:1483-91|
|Erickson, Kimberly D; Garcea, Robert L; Tsai, Billy (2009) Ganglioside GT1b is a putative host cell receptor for the Merkel cell polyomavirus. J Virol 83:10275-9|
|Qian, Mengding; Cai, Dawen; Verhey, Kristen J et al. (2009) A lipid receptor sorts polyomavirus from the endolysosome to the endoplasmic reticulum to cause infection. PLoS Pathog 5:e1000465|
|Bernardi, Kaleena M; Forster, Michele L; Lencer, Wayne I et al. (2008) Derlin-1 facilitates the retro-translocation of cholera toxin. Mol Biol Cell 19:877-84|
|Rainey-Barger, Emily K; Magnuson, Brian; Tsai, Billy (2007) A chaperone-activated nonenveloped virus perforates the physiologically relevant endoplasmic reticulum membrane. J Virol 81:12996-3004|
|Rainey-Barger, Emily K; Mkrtchian, Souren; Tsai, Billy (2007) Dimerization of ERp29, a PDI-like protein, is essential for its diverse functions. Mol Biol Cell 18:1253-60|