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J. Biol. Chem., Vol. 279, Issue 24, 24965-24975, June 11, 2004

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Characterization of GB Virus B Polyprotein Processing Reveals the Existence of a Novel 13-kDa Protein with Partial Homology to Hepatitis C Virus p7 Protein^*

David Ghibaudo, Lisette Cohen, François Penin¶, and Annette Martin||

From the Unité de Génétique Moléculaire des Virus Respiratoires, CNRS URA 1966, Institut Pasteur, 75724 Paris Cedex 15, France and ^¶CNRS UMR 5086, IFR 128 BioSciences, Lyon-Gerland, Institut de Biologie et Chimie des Protéines, 69367 Lyon Cedex 07, France

Although responsible for a major health problem worldwide, hepatitis C virus is difficult to study because of the absence of fully permissive cell cultures or experimental animal models other than the chimpanzee. GB virus B (GBV-B), a closely related hepatotropic virus that infects small New World primates and replicates efficiently in primary hepatocyte cultures, is an attractive surrogate model system. However, little is known about processing of the GBV-B polyprotein. Because an understanding of these events is critical to further development of model GBV-B systems, we characterized signal peptidase processing of the polyprotein segment containing the putative structural proteins. We identified the exact N termini of the mature GBV-B envelope proteins, E1 and E2, and the first nonstructural protein, NS2, by direct amino acid sequencing. Interestingly, these studies document the existence of a previously unrecognized 13-kDa protein (p13) located between E2 and NS2 within the polyprotein. We compared the sequence of the p13 protein to that of hepatitis C virus p7, a small membrane-spanning protein with a similar location in the polyprotein and recently identified ion channel activity. The C-terminal half of p13 shows clear homology with p7, suggesting a common function, but the substantially larger size of p13, with 4 rather than 2 predicted transmembrane segments, indicates a different structural organization and/or additional functions. The identification of p13 in the GBV-B polyprotein provides strong support for the hypothesis that ion channel-forming proteins are essential for the life cycle of flaviviruses, possibly playing a role in virion morphogenesis and/or virus entry into cells.

Received for publication, February 2, 2004 , and in revised form, April 1, 2004.

^* This work was supported in part by the French Ministère de la Recherche, Programme de Recherche Fondamentale en Microbiologie, Maladies Infectieuses et Parasitaires (PRFMMIP, "Emergence jeune équipe") and by the INSERM Grant 1A133C/CNRS (Réseau National: 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Fig. 1.

Supported by a French Ministère de la Recherche fellowship.

^|| To whom correspondence should be addressed: Unité de Génétique Moléculaire des Virus Respiratoires, CNRS URA 1966, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France. Tel.: 33-1-40-61-33-60; Fax: 33-1-40-61-30-45; E-mail: annettem{at}pasteur.fr.

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