The objective of this application is to clarify how a novel cytosolic chaperone complex promotes endoplasmic reticulum (ER) membrane penetration of the non-enveloped virus polyomavirus (Py). To cause infection, Py engages a host glycolipid receptor on the plasma membrane, becomes endocytosed, and traffics to the ER lumen. Here the viral particle undergoes conformational changes to penetrate the ER membrane and reach the cytosol. From the cytosol, the virus transports to the nucleus where transcription and replication of the viral genome ensue, leading to lytic infection or cellular transformation. How Py enters the cytosol from the ER is a crucial yet poorly understood event. Particularly enigmatic are cytosolic events that regulate this ER membrane penetration process. Accordingly this application is focused on elucidating the role of the so-called BHS cytosolic chaperone complex in ejecting Py into the cytosol from the ER.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM113722-03
Application #
9251299
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sakalian, Michael
Project Start
2015-05-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
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
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
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:
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; Tsai, Billy (2016) How Polyomaviruses Exploit the ERAD Machinery to Cause Infection. Viruses 8:
Ravindran, Madhu Sudhan; Tsai, Billy (2016) Correction: Viruses Utilize Cellular Cues in Distinct Combination to Undergo Systematic Priming and Uncoating. PLoS Pathog 12:e1005712
Bagchi, Parikshit; Inoue, Takamasa; Tsai, Billy (2016) EMC1-dependent stabilization drives membrane penetration of a partially destabilized non-enveloped virus. Elife 5:
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; 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

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