Acetaldehyde Disrupts Interferon Alpha Signaling in Hepatitis C Virus ‐Infected Liver Cells by Up‐Regulating USP18

ConclusionsWe conclude that Ach disrupts IFNα‐induced STAT1 phosphorylation by the up‐regulation of USP18 to block the innate immunity protection in HCV‐infected liver cells, thereby contributing to HCV‐alcohol pathogenesis. This, in part, may explain the mechanism of HCV‐infection exacerbation/progression in alcohol‐abusing patients. IFNα is an important innate immunity factor, which controls HCV replication and spread via the JAK‐STAT1 pathway activation. Here, we investigated the mechanisms which major ethanol metabolite, acetaldehyde, uses to enhance HCV RNA by decreasing IFNα‐induced STAT1 phosphorylation in liver cells. Acetaldehyde inhibits STAT1 phosphorylation by increasing USP18 expression. This dysregulates IFNαR2‐JAK1 cross‐talk and destabilizes STAT1 by de‐ISGylation followed by proteasome degradation of K48‐polyubiquitinated STAT1. Finally, acetaldehyde weakens antiviral IFNα signaling in infected hepatocytes thereby upregulating HCV RNA levels.
Source: Alcoholism: Clinical and Experimental Research - Category: Addiction Authors: Tags: Original Article Source Type: research