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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064296-08
Application #
8580897
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2005-04-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
8
Fiscal Year
2014
Total Cost
$309,588
Indirect Cost
$107,088
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Qi, Ling; Tsai, Billy; Arvan, Peter (2017) New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation. Trends Cell Biol 27:430-440
Ravindran, Madhu Sudhan; Engelke, Martin F; Verhey, Kristen J et al. (2017) Exploiting the kinesin-1 molecular motor to generate a virus membrane penetration site. Nat Commun 8:15496
Dupzyk, Allison; Williams, Jeffrey M; Bagchi, Parikshit et al. (2017) SGTA-Dependent Regulation of Hsc70 Promotes Cytosol Entry of Simian Virus 40 from the Endoplasmic Reticulum. J Virol 91:
Inoue, Takamasa; Tsai, Billy (2017) Regulated Erlin-dependent release of the B12 transmembrane J-protein promotes ER membrane penetration of a non-enveloped virus. PLoS Pathog 13:e1006439
Inoue, Takamasa; Tsai, Billy (2016) The Grp170 nucleotide exchange factor executes a key role during ERAD of cellular misfolded clients. Mol Biol Cell 27:1650-62
Williams, Jeffrey M; Tsai, Billy (2016) Intracellular trafficking of bacterial toxins. Curr Opin Cell Biol 41:51-6
Ravindran, Madhu Sudhan; Bagchi, Parikshit; Cunningham, Corey Nathaniel et al. (2016) Opportunistic intruders: how viruses orchestrate ER functions to infect cells. Nat Rev Microbiol 14:407-420
Bagchi, Parikshit; Inoue, Takamasa; Tsai, Billy (2016) EMC1-dependent stabilization drives membrane penetration of a partially destabilized non-enveloped virus. Elife 5:
Bagchi, Parikshit; Walczak, Christopher Paul; Tsai, Billy (2015) The endoplasmic reticulum membrane J protein C18 executes a distinct role in promoting simian virus 40 membrane penetration. J Virol 89:4058-68
Inoue, Takamasa; Tsai, Billy (2015) A nucleotide exchange factor promotes endoplasmic reticulum-to-cytosol membrane penetration of the nonenveloped virus simian virus 40. J Virol 89:4069-79

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