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J. Biol. Chem., Vol. 282, Issue 51, 37158-37169, December 21, 2007

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The Lipid Droplet Binding Domain of Hepatitis C Virus Core Protein Is a Major Determinant for Efficient Virus Assembly^*

Anna Shavinskaya, Steeve Boulant¹, Francois Penin^¶, John McLauchlan, and Ralf Bartenschlager²

From the Department of Molecular Virology, University of Heidelberg, 69120 Heidelberg, Germany, Medical Research Council Virology Unit, Institute of Virology, Church Street, Glasgow G11 5JR, Scotland, United Kingdom, and ^¶Institute de Biologie et Chimie des Protéines, UMR 5086, CNRS, Université de Lyon, IFR 128, BioSciences Lyon-Gerland, F-69397 Lyon, France

Hepatitis C virus core protein forms the viral capsid and is targeted to lipid droplets (LDs) by its domain 2 (D2). By using a comparative analysis of two hepatitis C virus genomes (JFH1 and Jc1) differing in their level of virus production in cultured human hepatoma cells, we demonstrate that the core of the genotype 2a isolate J6 that is present in Jc1 mediates efficient assembly and release of infectious virions. Mapping studies identified a single amino acid residue in D2 as a major determinant for enhanced assembly and release of infectious Jc1 particles. Confocal microscopy analyses demonstrate that core protein in JFH1-replicating cells co-localizes perfectly with LDs and induces their accumulation in the perinuclear area, whereas no such accumulation of LDs and only a partial co-localization of core and LDs were found with the Jc1 genome. By using a fluorescence recovery after photobleaching assay, we found that green fluorescent protein-tagged D2 variants are mobile on LDs and that J6- and JFH1-D2 differ in their mobility. Taken together, our results demonstrate that the binding strength of the D2 domain of core for LDs is crucial for determining the efficiency of virus assembly.

Received for publication, August 31, 2007 , and in revised form, October 17, 2007.

^* This work was supported in part by Ministry of Science, Research, and the Arts of Baden-Württemberg Grant Az 23-7532.24-22-21-12/1, Sonderfors-chungsbereich 638 Teilprojekt A5, Deutsche Forschungsgemeinschaft Grant Ba1502/2-1, the CellNetworks Cluster of Excellence Heidelberg, CNRS, and the Agence Nationale pour la Recherche sur le SIDA et les Hépatites Virales. 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 Supported by Marie Curie Intra-European Fellowship 025198.

² To whom correspondence should be addressed: Dept. of Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany. Tel.: 49-6221-56-4569; Fax: 49-6221-56-4570; E-mail: ralf_bartenschlager{at}med.uni-heidelberg.de.

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