Anti-hepatitis C virus activity of tamoxifen reveals the functional association of estrogen receptor with viral RNA polymerase NS5B

Hepatitis C virus ( HCV) is a major causative agent of hepatocellular carcinoma. HCV genome replication occurs in the replication complex ( RC) around the endoplasmic reticulum membrane. However, the mechanisms regulating the HCV RC remain widely unknown. Here, we used a chemical biology approach to show that estrogen receptor ( ESR) is functionally associated with HCV replication. We found that tamoxifen suppressed HCV genome replication. Part of ESR alpha resided on the endoplasmic reticulum membranes and interacted with HCV RNA polymerase NS5B. RNA interference- mediated knockdown of endogenous ESR alpha reduced HCV replication. Mechanistic analysis suggested that ESR alpha promoted NS5B association with the RC and that tamoxifen abrogated NS5B- RC association. Thus, ESR alpha regulated the presence of NS5B in the RC and stimulated HCV replication. Moreover, the ability of ESR alpha to regulate NS5B was suggested to serve as a potential novel target for anti-HCV therapeutics.