The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1
The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1
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DOI：
10.1128/jvi.00509-09
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发表时间：
2009-10-01
影响因子：
5.4
通讯作者：
Tan, Yee-Joo
中科院分区：
文献类型：
--
作者：
Mohd-Ismail, Nur Khairiah;Deng, Lin;Tan, Yee-Joo
丙型肝炎病毒（HCV）核心蛋白是已知的调节细胞凋亡，并有助于病毒复制和发病机制。在这项研究中，我们已经确定了Bcl-2的同源性3（BH 3）结构域的核心蛋白，是必不可少的促凋亡的属性。免疫共沉淀实验表明，核心蛋白相互作用的人髓样细胞因子1（Mcl-1），Bcl-2家族的促生存成员，但不与其他促生存成员（Bcl-X-L和Bcl-w）。此外，Mcl-1的过表达可防止核心诱导的细胞凋亡。通过使用肽模拟物，核心被发现从分离的线粒体中释放细胞色素c时，与坏的补充。因此，核心是真正的仅BH 3蛋白，其具有与Noxa的性质相似的性质，Noxa是Bcl-2家族的仅BH 3成员，其优先结合Mcl-1。在核心蛋白的BH 3结构域中有三个关键的疏水残基，它们对于核心蛋白的促凋亡性质是必需的。此外，基因型1b核心蛋白比基因型2a核心蛋白在诱导细胞凋亡方面更有效，这是由于在这些疏水残基之一（残基119）处的单个氨基酸差异。将J6/JFH-1感染性克隆（基因型2a）中的该残基替换为基因型1b核心蛋白中的相应氨基酸，产生了突变病毒J6/JFH-1（V119 L），其在感染细胞中诱导的凋亡水平显著高于亲本J6/JFH-1病毒。此外，在病毒感染的细胞中，J6/JFH-1的核心蛋白（V119 L）与Mcl-1相互作用，而J6/JFH-1的核心蛋白不与Mcl-1相互作用。两者合计，核心蛋白是一种新的BH 3-唯一的病毒同源物，有助于在HCV感染过程中诱导细胞凋亡。
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-X-L 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.