丙肝病毒(HCV)导致肝癌的机制尚不清楚。新近发现ATAD1蛋白能移除定位到线粒体的尾锚定蛋白，维持线粒体功能。HCV的NS5B是一种尾锚定蛋白。我们预实验发现，病毒感染或过表达时，大量NS5B定位到线粒体并导致线粒体断裂，伴随ATAD1在线粒体积累；敲除ATAD1增加NS5B的线粒体定位、c-Met和IFN-β的表达、细胞在免疫缺陷小鼠皮下的成瘤，但延迟病毒传播。过表达ATAD1则结果相反。据此我们推测ATAD1调控HCV感染并通过移除在线粒体上定位的NS5B来维持线粒体功能，抑制或延缓肝细胞癌变进程。本项目将阐明HCV感染下ATAD1和NS5B的线粒体定位和互作关系，及其调控线粒体功能的机制；研究IFN和癌标志基因的激活在NS5B/ATAD1-线粒体-肝癌路径中的作用；探讨丙肝性肝癌病人血细胞和肝组织中ATAD1与肝癌发生的潜在关联。项目将为研究丙肝性肝癌防治新策略提供理论和实验依据。

The mechanism of hepatitis C virus (HCV) causing liver cancer is not clear. Recently, it has been found that ATAD1 protein can remove the tail-anchored protein that mislocated to mitochondria and thus maintain the quality of mitochondria. The NS5B of HCV is a tail-anchored protein. We found that NS5B could be translocated to mitochondria and induced mitochondrial fragmentation, accompanied by the accumulation of ATAD1 in mitochondria, upon HCV infection or NS5B overexpression. Knockout of ATAD1 increased the mitochondrial localization of NS5B, the expression of proto-oncogene c-Met and interferon (IFN)-β, and the tumorigenic effect of NS5B-transfected cells in immunodeficient mice, whereas the viral spread was delayed. Overexpression of ATAD1 resulted in the opposite results. Based on these data, we speculate that ATAD1 regulates HCV infection and maintains mitochondrial function by removing NS5B that translocated to mitochondria to inhibit or delay the carcinogenesis of hepatocytes. In this project, we will elucidate the mitochondrial localization and interaction between ATAD1 and NS5B under HCV infection, and the mechanism of regulating mitochondrial function; we will clarify the role of IFN and oncogene activation in the pathogenesis of NS5B/ATAD1- mitochondrial function-hepatocellular carcinoma (HCC). Finally, we will investigate the correlation between the ATAD1 level in blood cells and hepatoma tissue and the occurrence of HCC by analyzing clinical samples from chronic hepatitis C patients and those hepatitis C-related HCC patients. The project will provide new insights into the study of new strategies for the prevention and treatment of hepatitis C-related HCC.