Ujino Saneyuki, Yamaguchi Saori, Shimotohno Kunitada, Takaku Hiroshi
Department of Life and Environmental Sciences, High Technology Research Center, Research Institute, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Chiba 275-0016, Japan.
J Biol Chem. 2009 Mar 13;284(11):6841-6. doi: 10.1074/jbc.M806452200. Epub 2009 Jan 16.
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 DeltaNS3 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.
丙型肝炎病毒（HCV）是慢性肝病的主要病因。在此，我们报告一种使用热休克蛋白90（Hsp90）抑制剂17-烯丙基氨基格尔德霉素（17-AAG）抑制HCV复制的新有效策略。Hsp90是一种分子伴侣，在稳定许多致癌信号蛋白的构象中起关键作用。我们在HCV复制子细胞培养系统中检测了17-AAG对HCV复制的抑制作用。在用17-AAG处理的HCV复制子细胞中，我们发现HCV RNA复制以剂量依赖性方式受到抑制，有趣的是，这些细胞中唯一降解的HCV蛋白是NS3（非结构蛋白3）。免疫沉淀实验表明，NS3直接与Hsp90相互作用，DeltaNS3蛋白酶表达载体表达的蛋白也是如此。这些结果表明，HCV RNA复制的抑制是由于17-AAG破坏Hsp90伴侣复合物导致NS3不稳定所致。
