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Title: Hepatitis C Virus Selectively Alters the Intracellular Localization of Desmosterol

Hepatitis C virus (HCV) increases intracellular desmosterol without affecting the steady-state abundance of other sterols, and the antiviral activity of inhibitors of desmosterol synthesis is suppressed by the addition of exogenous desmosterol. These observations suggest a model in which desmosterol has a specific function, direct or indirect, in HCV replication and that HCV alters desmosterol homeostasis to promote viral replication. Here, we use stimulated Raman scattering (SRS) microscopy in combination with isotopically labeled sterols to show that HCV causes desmosterol to accumulate in lipid droplets that are closely associated with the viral NS5A protein and that are visually distinct from the broad distribution of desmosterol in mock-infected cells and the more heterogeneous and disperse lipid droplets to which cholesterol traffics. Localization of desmosterol in NS5A-associated lipid droplets suggests that desmosterol may affect HCV replication via a direct mechanism. In conclusion, we anticipate that SRS microscopy and similar approaches can provide much-needed tools to study the localization of specific lipid molecules in cellulo and in vivo.
Authors:
 [1] ;  [2] ;  [1] ;  [2] ;  [1]
  1. Harvard Medical School, Boston, MA (United States)
  2. Harvard Univ., Cambridge, MA (United States)
Publication Date:
Grant/Contract Number:
SC0012411
Type:
Accepted Manuscript
Journal Name:
ACS Chemical Biology
Additional Journal Information:
Journal Volume: 11; Journal Issue: 7; Journal ID: ISSN 1554-8929
Publisher:
American Chemical Society (ACS)
Research Org:
Harvard Medical School, Boston, MA (United States). Dept. of Microbiology and Immunobiology
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1466800

Villareal, Valerie A., Fu, Dan, Costello, Deirdre A., Xie, Xiaoliang Sunney, and Yang, Priscilla L.. Hepatitis C Virus Selectively Alters the Intracellular Localization of Desmosterol. United States: N. p., Web. doi:10.1021/acschembio.6b00324.
Villareal, Valerie A., Fu, Dan, Costello, Deirdre A., Xie, Xiaoliang Sunney, & Yang, Priscilla L.. Hepatitis C Virus Selectively Alters the Intracellular Localization of Desmosterol. United States. doi:10.1021/acschembio.6b00324.
Villareal, Valerie A., Fu, Dan, Costello, Deirdre A., Xie, Xiaoliang Sunney, and Yang, Priscilla L.. 2016. "Hepatitis C Virus Selectively Alters the Intracellular Localization of Desmosterol". United States. doi:10.1021/acschembio.6b00324. https://www.osti.gov/servlets/purl/1466800.
@article{osti_1466800,
title = {Hepatitis C Virus Selectively Alters the Intracellular Localization of Desmosterol},
author = {Villareal, Valerie A. and Fu, Dan and Costello, Deirdre A. and Xie, Xiaoliang Sunney and Yang, Priscilla L.},
abstractNote = {Hepatitis C virus (HCV) increases intracellular desmosterol without affecting the steady-state abundance of other sterols, and the antiviral activity of inhibitors of desmosterol synthesis is suppressed by the addition of exogenous desmosterol. These observations suggest a model in which desmosterol has a specific function, direct or indirect, in HCV replication and that HCV alters desmosterol homeostasis to promote viral replication. Here, we use stimulated Raman scattering (SRS) microscopy in combination with isotopically labeled sterols to show that HCV causes desmosterol to accumulate in lipid droplets that are closely associated with the viral NS5A protein and that are visually distinct from the broad distribution of desmosterol in mock-infected cells and the more heterogeneous and disperse lipid droplets to which cholesterol traffics. Localization of desmosterol in NS5A-associated lipid droplets suggests that desmosterol may affect HCV replication via a direct mechanism. In conclusion, we anticipate that SRS microscopy and similar approaches can provide much-needed tools to study the localization of specific lipid molecules in cellulo and in vivo.},
doi = {10.1021/acschembio.6b00324},
journal = {ACS Chemical Biology},
number = 7,
volume = 11,
place = {United States},
year = {2016},
month = {4}
}