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Journal of Virology, June 2006, p. 6013-6023, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.00053-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Palmitoylation and Polymerization of Hepatitis C Virus NS4B Protein

Guann-Yi Yu,1 Ki-Jeong Lee,1 Lu Gao,1,2 and Michael M. C. Lai1,3*

Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California,1 Ludwig Institute for Cancer Research, La Jolla, California,2 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan3

Received 9 January 2006/ Accepted 28 March 2006

Hepatitis C Virus (HCV) NS4B protein induces a specialized membrane structure which may serve as the replication platform for HCV RNA replication. In the present study, we demonstrated that NS4B has lipid modifications (palmitoylation) on two cysteine residues (cysteines 257 and 261) at the C-terminal end. Site-specific mutagenesis of these cysteine residues on individual NS4B proteins and on an HCV subgenomic replicon showed that the lipid modifications, particularly of Cys261, are important for protein-protein interaction in the formation of the HCV RNA replication complex. We further demonstrated that NS4B can undergo polymerization. The main polymerization determinants were mapped in the N-terminal cytosolic domain of NS4B protein; however, the lipid modifications on the C terminus also facilitate the polymerization process. The lipid modification and the polymerization activity could be two properties of NS4B important for its induction of the specialized membrane structure involved in viral RNA replication.

* Corresponding author. Mailing address: Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90033-1054. Phone: (323) 442-1748. Fax: (323) 442-1721. E-mail: michlai{at}usc.edu.

Journal of Virology, June 2006, p. 6013-6023, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.00053-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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