Endocytic Rab proteins are required for hepatitis C virus replication complex formation

Abstract During infection, hepatitis C virus (HCV) NS4B protein remodels host membranes to form HCV replication complexes (RC) which appear as foci under fluorescence microscopy (FM). To understand the role of Rab proteins in forming NS4B foci, cells expressing the HCV replicon were examined biochem...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2010-03, Vol.398 (1), p.21-37
Main Authors: Manna, David, Aligo, Jason, Xu, Chenjia, Park, Wei Sun, Koc, Hasan, Do Heo, Won, Konan, Kouacou V
Format: Article
Language:English
Subjects:
Cell Line
DN Rab proteins
Gene Expression Regulation, Viral - physiology
HCV NS4B
HCV RC
HCV RDRP Activity
Hepacivirus - metabolism
Hepatitis C virus
Humans
Infectious Disease
Membranous web
NS4B FOCI
rab GTP-Binding Proteins - genetics
rab GTP-Binding Proteins - metabolism
Rab proteins
RNA Replicase - physiology
RNA silencing
RNA, Viral - genetics
RNA, Viral - metabolism
Subcellular fractionation
Viral Proteins - genetics
Viral Proteins - metabolism
Virus Replication - physiology
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Summary:Abstract During infection, hepatitis C virus (HCV) NS4B protein remodels host membranes to form HCV replication complexes (RC) which appear as foci under fluorescence microscopy (FM). To understand the role of Rab proteins in forming NS4B foci, cells expressing the HCV replicon were examined biochemically and via FM. First, we show that an isolated NS4B-bound subcellular fraction is competent for HCV RNA synthesis. Further, this fraction is differentially enriched in Rab1, 2, 5, 6 and 7. However, when examined via FM, NS4B foci appear to be selectively associated with Rab5 and Rab7 proteins. Additionally, dominant negative (DN) Rab6 expression impairs Rab5 recruitment into NS4B foci. Further, silencing of Rab5 or Rab7 resulted in a significant decrease in HCV genome replication. Finally, expression of DN Rab5 or Rab7 led to a reticular NS4B subcellular distribution, suggesting that endocytic proteins Rab5 and Rab7, but not Rab11, may facilitate NS4B foci formation.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2009.11.034