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J. Biol. Chem., Vol. 281, Issue 38, 27679-27692, September 22, 2006

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Signal Peptide Peptidase-catalyzed Cleavage of Hepatitis C Virus Core Protein Is Dispensable for Virus Budding but Destabilizes the Viral Capsid^*

Christelle Vauloup-Fellous¹, Véronique Pène², Julie Garaud-Aunis, Francis Harper^¶, Sabine Bardin, Yannick Suire³, Evelyne Pichard^¶, Alain Schmitt^||, Philippe Sogni^**, Gérard Pierron^¶, Pascale Briand, and Arielle R. Rosenberg⁴

From the INSERM, Equipe AVENIR, Institut Cochin, 75014 Paris, Université Paris-XI, Faculté de Médecine, AP-HP, Hôpital Antoine Béclère, Microbiologie, 92141 Clamart, ^¶CNRS, FRE 2937, Institut André Lwoff, 94801 Villejuif, ^||INSERM, U 567, CNRS, UMR 8104, Institut Cochin, Plateforme de MicroscopieÉlectronique, 75014 Paris, ^**Université Paris-Descartes, Faculté de Médecine, AP-HP, Groupe Hospitalier Cochin Saint-Vincent-de-Paul, Hépatologie, 75014 Paris, Université Paris-Descartes, Faculté de Médecine, AP-HP, Groupe Hospitalier Cochin Saint-Vincent-de-Paul, Virologie, 75014 Paris, France

The capsid of hepatitis C virus (HCV) particles is considered to be composed of the mature form (p21) of core protein. Maturation to p21 involves cleavage of the transmembrane domain of the precursor form (p23) of core protein by signal peptide peptidase (SPP), a cellular protease embedded in the endoplasmic reticulum membrane. Here we have addressed whether SPP-catalyzed maturation to p21 is a prerequisite for HCV particle morphogenesis in the endoplasmic reticulum. HCV structural proteins were expressed by using recombinant Semliki Forest virus replicon in mammalian cells or recombinant baculovirus in insect cells, because these systems have been shown to allow the visualization of HCV budding events and the isolation of HCV-like particles, respectively. Inhibition of SPP-catalyzed cleavage of core protein by either an SPP inhibitor or HCV core mutations not only did not prevent but instead tended to facilitate the observation of viral buds and the recovery of virus-like particles. Remarkably, although maturation to p21 was only partially inhibited by mutations in insect cells, p23 was the only form of core protein found in HCV-like particles. Finally, newly developed assays demonstrated that p23 capsids are more stable than p21 capsids. These results show that SPP-catalyzed cleavage of core protein is dispensable for HCV budding but decreases the stability of the viral capsid. We propose a model in which p23 is the form of HCV core protein committed to virus assembly, and cleavage by SPP occurs during and/or after virus budding to predispose the capsid to subsequent disassembly in a new cell.

Received for publication, March 20, 2006 , and in revised form, July 14, 2006.

^* This work was supported by an INSERM "AVENIR" grant, by a grant from the French Ministère de la Recherche via the "Réseau National Hépatites," and by the Fondation Bettencourt-Schueller. This work was presented in part in abstract form at the 56th Annual Meeting of the American Association for the Study of Liver Diseases, November 11–15, 2005, San Francisco, CA. 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 in part by a master studentship from the Fondation pour la Recherche Médicale.

² Supported by a studentship co-financed by the INSERM and the Région Ile-de-France.

³ Supported by a fellowship from the Fondation des Treilles.

⁴ To whom correspondence should be addressed. Tel.: 33-1-40516493; Fax: 33-1-40516407; E-mail: arielle{at}cochin.inserm.fr.

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