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 #
5R01AI064296-09
Application #
8766538
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
2005-04-01
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
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
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
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
Ravindran, Madhu Sudhan; Bagchi, Parikshit; Inoue, Takamasa et al. (2015) A Non-enveloped Virus Hijacks Host Disaggregation Machinery to Translocate across the Endoplasmic Reticulum Membrane. PLoS Pathog 11:e1005086
Inoue, Takamasa; Dosey, Annie; Herbstman, Jeffrey F et al. (2015) ERdj5 Reductase Cooperates with Protein Disulfide Isomerase To Promote Simian Virus 40 Endoplasmic Reticulum Membrane Translocation. J Virol 89:8897-908
He, Kaiyu; Ravindran, Madhu Sudhan; Tsai, Billy (2015) A bacterial toxin and a nonenveloped virus hijack ER-to-cytosol membrane translocation pathways to cause disease. Crit Rev Biochem Mol Biol 50:477-88
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
Ito, Yuki; Vela, Jose Luis; Matsumura, Fumiko et al. (2013) Helicobacter pylori cholesteryl α-glucosides contribute to its pathogenicity and immune response by natural killer T cells. PLoS One 8:e78191
Inoue, Takamasa; Tsai, Billy (2013) How viruses use the endoplasmic reticulum for entry, replication, and assembly. Cold Spring Harb Perspect Biol 5:a013250

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