Ethanol facilitates HCV replication via upregulation of GW182 and HSP90 in human hepatoma cells
Department of Medicine, Division of Gastroenterology
Medical Subject Headings
Hepatitis C; Ethanol; Autoantigens; RNA-Binding Proteins
Digestive System Diseases | Gastroenterology | Hepatology | Virus Diseases
Alcohol use and hepatitis C virus (HCV) infection synergize to cause liver damage and microRNA-122 (miR-122) appears to play a key role in this process. Argonaute 2 (Ago2), a key component of the RNA-induced silencing complex, has been shown to be important in modulating miR-122 function during HCV infection. However, GW182, a critical component of processing bodies (GW-bodies) that is recruited by Ago2 to target mRNA has not been assessed in HCV infection. To characterize the role of GW182 in the pathogenesis of HCV infection, we determined its transcription and protein expression in an HCV J6/JFH1 culture system. Here we show that transcript and protein levels of GW182 as well as HCV RNA and protein expression increased with alcohol exposure. Specific silencing of mRNA expression by short interference (si) RNA against GW182 significantly decreased HCV RNA and protein expression. Over-expression of GW182 significantly increased HCV RNA and protein expression in HCV J6/JFH1 infected Huh-7.5 cells. Furthermore, GW182 co-localized and co-immunoprecipitated with HSP90 which increased on alcohol exposure with and without HCV infection and enhanced HCV gene expression. The use of an HSP90 inhibitor or knockdown of HSP90 decreased GW182 and miR-122 expression and significantly reduced HCV replication. Overall, our results suggest that GW182 protein that is linked to miR-122 biogenesis and HSP90, which has been shown to stabilize the RNA-induced silencing complex, are novel host proteins that regulate HCV infection during alcohol abuse. (HEPATOLOGY 2012.).