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Journal of Virology, October 2009, p. 9993-10006, Vol. 83, No. 19
0022-538X/09/$08.00+0 doi:10.1128/JVI.00509-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1 
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Nur Khairiah Mohd-Ismail,1,2
Lin Deng,3
Sunil Kumar Sukumaran,4
Victor C. Yu,4,5
Hak Hotta,3 and
Yee-Joo Tan1*
Collaborative Anti-Viral Research Group, Institute of Molecular and Cell Biology, Singapore,1 NUS Graduate School for Integrative Sciences and Engineering, Singapore,2 Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan,3 Mechanisms of Apoptosis in Mammalian Cell Group, Institute of Molecular and Cell Biology, Singapore,4 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore5
Received 11 March 2009/ Accepted 8 July 2009
The hepatitis C virus (HCV) core protein is known to modulate apoptosis and contribute to viral replication and pathogenesis. In this study, we have identified a Bcl-2 homology 3 (BH3) domain in the core protein that is essential for its proapoptotic property. Coimmunoprecipitation experiments showed that the core protein interacts specifically with the human myeloid cell factor 1 (Mcl-1), a prosurvival member of the Bcl-2 family, but not with other prosurvival members (Bcl-XL and Bcl-w). Moreover, the overexpression of Mcl-1 protects against core-induced apoptosis. By using peptide mimetics, core was found to release cytochrome c from isolated mitochondria when complemented with Bad. Thus, core is a bona fide BH3-only protein having properties similar to those of Noxa, a BH3-only member of the Bcl-2 family that binds preferentially to Mcl-1. There are three critical hydrophobic residues in the BH3 domain of the core protein, and they are essential for the proapoptotic property of the core protein. Furthermore, the genotype 1b core protein is more effective than the genotype 2a core protein in inducing apoptosis due to a single-amino-acid difference at one of these hydrophobic residues (residue 119). Replacing this residue in the J6/JFH-1 infectious clone (genotype 2a) with the corresponding amino acid in the genotype 1b core protein produced a mutant virus, J6/JFH-1(V119L), which induced significantly higher levels of apoptosis in the infected cells than the parental J6/JFH-1 virus. Furthermore, the core protein of J6/JFH-1(V119L), but not that of J6/JFH-1, interacted with Mcl-1 in virus-infected cells. Taken together, the core protein is a novel BH3-only viral homologue that contributes to the induction of apoptosis during HCV infection.
* Corresponding author. Mailing address: Cancer and Developmental Cell Biology Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 136873, Singapore. Phone: 65-65869625. Fax: 65-67791117. E-mail: mcbtanyj{at}imcb.a-star.edu.sg
Published ahead of print on 15 July 2009.
Supplemental material for this article may be found at http://jvi.asm.org/.
Journal of Virology, October 2009, p. 9993-10006, Vol. 83, No. 19
0022-538X/09/$08.00+0 doi:10.1128/JVI.00509-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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