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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064296-14
Application #
9859293
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Natarajan, Ramya
Project Start
2006-06-15
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
14
Fiscal Year
2020
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
Dupzyk, Allison; Tsai, Billy (2018) Bag2 Is a Component of a Cytosolic Extraction Machinery That Promotes Membrane Penetration of a Nonenveloped Virus. J Virol 92:
Ravindran, Madhu Sudhan; Spriggs, Chelsey C; Verhey, Kristen J et al. (2018) Dynein engages and disassembles cytosol-localized SV40 to promote infection. J Virol :
Inoue, Takamasa; Zhang, Pengwei; Zhang, Wei et al. (2018) ?-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection. J Cell Biol 217:3545-3559
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
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
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 (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

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