Kaposi's sarcoma-associated herpesvirus mitochondrial K7 protein targets a cellular calcium-modulating cyclophilin ligand to modulate intracellular calcium concentration and inhibit apoptosis
Kaposi's sarcoma-associated herpesvirus mitochondrial K7 protein targets a cellular calcium-modulating cyclophilin ligand to modulate intracellular calcium concentration and inhibit apoptosis
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DOI：
10.1128/jvi.76.22.11491-11504.2002
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发表时间：
2002-11-01
影响因子：
5.4
通讯作者：
Jung, JU
中科院分区：
文献类型：
--
作者：
Feng, PH;Park, J;Jung, JU
在病毒感染方面，受感染的细胞可能成为宿主免疫反应的目标，也可能经历被称为细胞凋亡的程序性细胞死亡过程，作为限制病毒复制能力的一种防御机制。为了防止这一点，病毒进化出了复杂的机制来颠覆细胞凋亡的过程。在这里，我们报告了一种新的K7抗凋亡蛋白的鉴定，该蛋白在裂解复制过程中表达。KSHV K7基因编码一种小的线粒体膜蛋白，其表达可有效抑制多种致凋剂诱导的细胞凋亡。酵母双杂交筛选表明，K7以细胞内钙调节亲环素配体(CAML)为靶标，CAML是一种调节细胞内钙离子浓度的蛋白质。与CAML相似，K7的表达显著增强了细胞内钙离子浓度在细胞凋亡刺激下升高的动力学和幅度。突变分析表明，K7与CAML的相互作用是其抑制细胞凋亡所必需的。这表明K7靶向细胞CAML，增加细胞内钙离子的反应，从而保护细胞免受线粒体损伤和凋亡。这是一种新的病毒抗凋亡策略，KSHV线粒体K7蛋白以细胞内钙调节蛋白为靶点，赋予细胞对凋亡的抵抗力，从而完成病毒的裂解复制，最终维持感染宿主的持续感染。
On viral infection, infected cells can become the target of host immune responses or can go through a programmed cell death process, called apoptosis, as a defense mechanism to limit the ability of the virus to replicate. To prevent this, viruses have evolved elaborate mechanisms to subvert the apoptotic process. Here, we report the identification of a novel antiapoptotic K7 protein of Kaposils sarcoma-associated herpesvirus (KSHV) which expresses during lytic replication. The KSHV K7 gene encodes a small mitochondrial membrane protein, and its expression efficiently inhibits apoptosis induced by a variety of apoptogenic agents. The yeast two-hybrid screen has demonstrated that K7 targets cellular calcium-modulating cyclophilin ligand (CAML), a protein that regulates the intracellular Ca2+ concentration. Similar to CAML, K7 expression significantly enhances the kinetics and amplitudes of the increase in intracellular Ca2+ concentration on apoptotic stimulus. Mutational analysis showed that K7 interaction with CAML is required for its function in the inhibition of apoptosis. This indicates that K7 targets cellular CAML to increase the cytosolic Ca2+ response, which consequently protects cells from mitochondrial damage and apoptosis. This is a novel viral antiapoptosis strategy where the KSHV mitochondrial K7 protein targets a cellular Ca2+-modulating protein to confer resistance to apoptosis, which allows completion of the viral lytic replication and, eventually, maintenance of persistent infection in infected host.