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J. Biol. Chem., Vol. 279, Issue 40, 41384-41392, October 1, 2004

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Regulation of Hepatitis C Virus Polyprotein Processing by Signal Peptidase Involves Structural Determinants at the p7 Sequence Junctions^*

Séverine Carrère-Kremer, Claire Montpellier, Lazaro Lorenzo, Bénédicte Brulin, Laurence Cocquerel, Sandrine Belouzard, François Penin, and Jean Dubuisson¶

From the CNRS-UPR2511, Institut de Biologie de Lille, 59021 Lille, France and the CNRS-UMR5086, IFR128 BioSciences Lyon-Gerland, Institut de Biologie et de Chimie des Protéines, 69367 Lyon, France

The hepatitis C virus genome encodes a polyprotein precursor that is co- and post-translationally processed by cellular and viral proteases to yield 10 mature protein products (C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). Although most cleavages in hepatitis C virus polyprotein precursor proceed to completion during or immediately after translation, the cleavages mediated by a host cell signal peptidase are partial at the E2/p7 and p7/NS2 sites, leading to the production of an E2p7NS2 precursor. The sequences located immediately N-terminally of E2/p7 and p7/NS2 cleavage sites can function as signal peptides. When fused to a reporter protein, the signal peptides of p7 and NS2 were efficiently cleaved. However, when full-length p7 was fused to the reporter protein, partial cleavage was observed, indicating that a sequence located N-terminally of the signal peptide reduces the efficiency of p7/NS2 cleavage. Sequence analyses and mutagenesis studies have also identified structural determinants responsible for the partial cleavage at both the E2/p7 and p7/NS2 sites. Finally, the short distance between the cleavage site of E2/p7 or p7/NS2 and the predicted transmembrane -helix within the P' region might impose additional structural constraints to the cleavage sites. The insertion of a linker polypeptide sequence between P-3' and P-4' of the cleavage site released these constraints and led to improved cleavage efficiency. Such constraints in the processing of a polyprotein precursor are likely essential for hepatitis C virus to post-translationally regulate the kinetics and/or the level of expression of p7 as well as NS2 and E2 mature proteins.

Received for publication, June 7, 2004 , and in revised form, July 1, 2004.

^* This work was supported by the CNRS, European Union Grant QLK2–1999-00356, a grant from the Association Nationale de Recherche sur le SIDA, and a grant from the Association pour la Recherche sur le Cancer. 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.

^¶ To whom correspondence should be addressed: CNRS-UPR2511, Institut de Biologie de Lille, 1 rue Calmette, BP447, 59021 Lille, France. Tel.: 33-3-20-87-11-60; Fax: 33-3-20-87-12-01; E-mail: jean.dubuisson{at}ibl.fr.

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