Hepatitis C virus (HCV) is a major cause of chronic liver disease. However, little is known about the details of its assembly and secretion. Golgi-related proteins have been recently proven to have a key function in HCV secretion. Golgi protein 73 (GP73), a resident Golgi membrane protein, is a potential serum biomarker for the diagnosis of liver diseases and hepatocellular carcinoma. Previous studies have demonstrated the upregulation of GP73 in the liver samples and sera of HCV-infected patients. However, the function and regulatory mechanism of GP73 in HCV infection at the cellular level remain unknown. In this study, we examined the expression level of GP73 in HCV infected cells and its effect on HCV life cycle in cell culture systems. Both the protein expression and mRNA levels of GP73 significantly increased in HCV subgenomic replicon-harboring cells and HCV-infected cells, which imply that GP73 was upregulated by HCV infection. HCV production was significantly enhanced when GP73 was overexpressed, but dramatically inhibited when GP73 was silenced. However, the overexpression and knockdown of GP73 showed no evident effect on the entry, protein translation, RNA replication, and assembly of HCV, which indicates that GP73 enhanced the secretion process. Moreover, the coiled-coil domain of GP73 was required to increase HCV secretion. GP73 increased and interacted with apolipoprotein E, an identified host factor that assists in HCV secretion. These results demonstrate the critical function of GP73 in HCV secretion and provide new insights into the therapeutic design of antiviral strategies.
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