A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection
A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection
复制标题
DOI：
10.1002/hep.22107
复制
发表时间：
2008-03-01
期刊：
影响因子：
13.5
通讯作者：
Jang, Sung Key
中科院分区：
文献类型：
--
作者：
Lee, Song Hee;Song, Ran;Jang, Sung Key
丙型肝炎病毒（HCV）E2蛋白已被证明可以阻断细胞凋亡，并被认为有助于病毒的持续感染。在这里，我们报告说，E2的抗凋亡活性是通过激活核因子κ B（NF-κ B B）介导的，核因子κ B（NF-κ B）指导生存基因产物的表达，如肿瘤坏死因子（TNF-α）受体相关因子2（TRAF 2），X染色体连锁凋亡抑制蛋白（XIAP），FLICE样抑制蛋白（FLIP）和生存素。在HCV感染的细胞和产生HCV E2蛋白的细胞系中观察到这些蛋白的水平增加。NF-κ B B的激活是由HCV-E2诱导的分子伴侣葡萄糖调节蛋白94（GRP 94）的表达介导的。单独过表达GRP 94导致抗凋亡蛋白的表达，并阻断肿瘤坏死相关凋亡诱导配体（TRAIL）诱导的细胞凋亡。有趣的是，在来源于HCV患者肝组织的支持HCV增殖的细胞中观察到GRP 94水平增加。此外，GRP 94的小干扰RNA（siRNA）敲低使HCV E2的抗凋亡活性无效。结论：这些数据表明，HCV E2通过过量产生GRP 94阻断HCV感染和宿主免疫系统诱导的细胞凋亡，并且HCV E2在持续HCV感染中起重要作用。
The hepatitis C virus (HCV) E2 protein has been shown to block apoptosis and has been suggested to facilitate persistent infection of the virus. Here, we report that the anti-apoptotic activity of E2 is mediated by activation of nuclear factor kappa B (NF-kappa B) that directs expression of survival gene products such as tumor necrosis factor (TNF-alpha) receptor-associated factor 2 (TRAF2), X-chromosome-linked inhibitor of apoptosis protein (XIAP), FLICE-like inhibitory protein (FLIP), and survivin. Increased levels of these proteins were observed in HCV-infected cells and a cell line producing HCV E2 protein. The activation of NF-kappa B was mediated by HCV-E2-induced expression of the molecular chaperone glucose-regulated protein 94 (GRP94). Overexpression of GRP94 alone resulted in expression of anti-apoptotic proteins and blocked apoptosis induced by tumor-necrosis-related apoptosis-inducing ligand (TRAIL). Interestingly, increased levels of GRP94 were observed in cells supporting HCV proliferation that originated from liver tissues from HCV patients. Moreover, small interfering RNA (siRNA) knock-down of GRP94 nullified the anti-apoptotic activity of HCV E2. Conclusion: These data indicate that HCV E2 blocks apoptosis induced by HCV infection and the host immune system through overproduction of GRP94, and that HCV E2 plays an important role in persistent HCV infection.