HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 50, 36354-36361, December 14, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/50/36354    most recent M705221200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sklan, E. H. Articles by Glenn, J. S. Search for Related Content PubMed PubMed Citation Articles by Sklan, E. H. Articles by Glenn, J. S. Social Bookmarking                      What's this?

TBC1D20 Is a Rab1 GTPase-activating Protein That Mediates Hepatitis C Virus Replication^*

Ella H. Sklan¹, Ramon L. Serrano², Shirit Einav, Suzanne R. Pfeffer, David G. Lambright^¶, and Jeffrey S. Glenn^||3

From the Department of Medicine, Division of Gastroenterology and Hepatology, and the Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, the ^||Veterans Affairs Medical Center, Palo Alto, California 94304, and the ^¶Program in Molecular Medicine and the Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Like other viruses, productive hepatitis C virus (HCV) infection depends on certain critical host factors. We have recently shown that an interaction between HCV nonstructural protein NS5A and a host protein, TBC1D20, is necessary for efficient HCV replication. TBC1D20 contains a TBC (Tre-2, Bub2, and Cdc16) domain present in most known Rab GTPase-activating proteins (GAPs). The latter are master regulators of vesicular membrane transport, as they control the activity of membrane-associated Rab proteins. To better understand the role of the NS5A-TBC1D20 interaction in the HCV life cycle, we used a biochemical screen to identify the TBC1D20 Rab substrate. TBC1D20 was found to be the first known GAP for Rab1, which is implicated in the regulation of anterograde traffic between the endoplasmic reticulum and the Golgi complex. Mutation of amino acids implicated in Rab GTPase activation by other TBC domain-containing GAPs abrogated the ability of TBC1D20 to activate Rab1 GTPase. Overexpression of TBC1D20 blocked the transport of exogenous vesicular stomatitis virus G protein from the endoplasmic reticulum, validating the involvement of TBC1D20 in this pathway. Rab1 depletion significantly decreased HCV RNA levels, suggesting a role for Rab1 in HCV replication. These results highlight a novel mechanism by which viruses can hijack host cell machinery and suggest an attractive model whereby the NS5A-TBC1D20 interaction may promote viral membrane-associated RNA replication.

Received for publication, June 26, 2007 , and in revised form, September 26, 2007.

^* This work was supported in part by a Burroughs Wellcome Fund award and National Institutes of Health Grants RO1-DK064223 (to J. S. G.) and R37-DK37332 (to S. R. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of an American Liver Foundation postdoctoral research fellow award and an Israel Science Foundation Bikura postdoctoral fellowship.

² Supported by a grant from the Susan G. Komen Breast Cancer Foundation.

³ To whom correspondence should be addressed: Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR Bldg., Rm. 3115, 269 Campus Dr., Palo Alto, CA 94305-5187. Tel.: 650-725-3373; Fax: 650-723-3032; E-mail: jeffrey.glenn{at}stanford.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?