ROS/NF-κB Signaling Pathway-Mediated Transcriptional Activation of TRIM37 Promotes HBV-Associated Hepatic Fibrosis

Abstract

Hepatic fibrosis is an inflammatory response that leads to liver cirrhosis in the most advanced condition. Liver cirrhosis is a leading cause of deaths associated with liver diseases; hence, understanding the underlying mechanisms of hepatic fibrosis is critical to develop effective therapies. Tripartite motif (TRIM) family proteins have been shown to be involved in liver fibrosis; however, the exact role of several TRIM proteins in this process remained unexplored. In this study, we investigated the role of TRIM37 in hepatitis B virus (HBV)-associated hepatic fibrosis. We analyzed TRIM37 expression in hepatic fibrosis patients and performed functional and mechanistic studies in tissue culture and mouse models to identify the role of TRIM37 in hepatic fibrosis. We found an increased expression of TRIM37 in hepatic fibrosis patients. Mechanistically, we showed that TRIM37 physically interacts with SMAD7 and promotes ubiquitination-mediated degradation of SMAD7, and that SMAD7 is a key mediator of TRM37-induced hepatic fibrosis. Furthermore, we showed nuclear factor κB (NF-κB) activation mediated by reactive oxygen species (ROS) is necessary for the transcriptional induction of TRIM37 during HBV infection. Our study shows TRIM37 as an important promoter of HBV-associated hepatic fibrosis.

Keywords: NF-κB; SMAD7; TRIM37; hepatic fibrosis; hepatitis B virus; reactive oxygen species.