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 ESRalpha resided on the endoplasmic reticulum membranes and interacted with HCV RNA polymerase NS5B. RNA interference-mediated knockdown of endogenous ESRalpha reduced HCV replication. Mechanistic analysis suggested that ESRalpha promoted NS5B association with the RC and that tamoxifen abrogated NS5B-RC association. Thus, ESRalpha regulated the presence of NS5B in the RC and stimulated HCV replication. Moreover, the ability of ESRalpha to regulate NS5B was suggested to serve as a potential novel target for anti-HCV therapeutics.
Watashi
Koichi
K
Department of Viral Oncology, Institute for Virus Research, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, Japan.
Inoue
Daisuke
D
Hijikata
Makoto
M
Goto
Kaku
K
Aly
Hussein H
HH
Shimotohno
Kunitada
K
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D013629:Tamoxifen / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D013629:Tamoxifen; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase