Heat-shock Protein 90 Is Essential for Stabilization of the Hepatitis C Virus Nonstructural Protein NS3
Heat-shock Protein 90 Is Essential for Stabilization of the Hepatitis C Virus Nonstructural Protein NS3
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DOI：
10.1074/jbc.m806452200
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发表时间：
2009-03-13
影响因子：
4.8
通讯作者：
Takaku, Hiroshi
中科院分区：
文献类型：
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作者：
Ujino, Saneyuki;Yamaguchi, Saori;Takaku, Hiroshi
丙型肝炎病毒(HCV)是慢性肝病的主要原因。在这里，我们报告了一种新的有效的策略，使用热休克蛋白90(Hsp90)的抑制剂17-烯丙基氨基凝胶(17-AAG)来抑制丙型肝炎病毒的复制。HSP90是一种分子伴侣，在稳定多种致癌信号蛋白的构象中起着关键作用。我们在一个丙型肝炎病毒复制子细胞培养系统中检测了17-AAG对丙型肝炎病毒复制的抑制作用。在用17-AAG处理的丙型肝炎病毒复制子细胞中，我们发现丙型肝炎病毒RNA的复制受到剂量依赖的抑制，有趣的是，在这些细胞中唯一被降解的丙型肝炎病毒蛋白是NS3(非结构蛋白3)。免疫沉淀实验表明，NS3与Hsp90直接相互作用，Delta NS3蛋白表达载体表达的蛋白质也直接与Hsp90相互作用。这些结果表明，丙型肝炎病毒RNA复制的抑制是由于17-AAG破坏Hsp90伴侣复合体中NS3的不稳定所致。
The hepatitis C virus (HCV) is a major cause of chronic liver disease. Here, we report a new and effective strategy for inhibiting HCV replication using 17-allylaminogeldanamycin (17-AAG), an inhibitor of heat-shock protein 90 (Hsp90). Hsp90 is a molecular chaperone with a key role in stabilizing the conformation of many oncogenic signaling proteins. We examined the inhibitory effects of 17-AAG on HCV replication in an HCV replicon cell culture system. In HCV replicon cells treated with 17-AAG, we found that HCV RNA replication was suppressed in a dose-dependent manner, and interestingly, the only HCV protein degraded in these cells was NS3 (nonstructural protein 3). Immunoprecipitation experiments showed that NS3 directly interacted with Hsp90, as did proteins expressed from Delta NS3 protease expression vectors. These results suggest that the suppression of HCV RNA replication is due to the destabilization of NS3 in disruption of the Hsp90 chaperone complex by 17-AAG.