Hepatocyte OTUD1 promotes hepatic stellate cell activation and liver fibrosis by stabilizing HSP90β

Abstract

Crosstalk between parenchymal and nonparenchymal cells of the liver mediates the activation of hepatic stellate cells (HSCs). Activated HSCs transform into myofibroblasts and produce the extracellular matrix (ECM), and massive ECM accumulation can affect liver function and eventually lead to liver fibrosis. Ovarian tumor domain protein 1 (OTUD1) is a deubiquitinases (DUB) that controls diseases progression. However, the physiological functions and underlying mechanisms of action of OTUD1 in liver fibrosis have not been investigated. In this study, bile duct ligation (BDL) and carbon tetrachloride (CCl 4 ) injection were used to investigate the role of OTUD1 in liver fibrosis. The human liver cell line, LO-2, was co-cultured with human HSCs LX-2 to investigate the role of OTUD1 in HSCs activation and its related mechanisms. Our results show that OTUD1 was upregulated in fibrotic liver tissues. Additionally, OTUD1 knockout improved BDL- and CCl 4 -induced liver injury and fibrosis in vivo. In vitro, OTUD1 overexpression induced LX-2 activation by promoting TGF-β1 secretion in LO-2 cells. Meanwhile, we found that OTUD1 deubiquitinated and stabilized HSP90β. Our results suggest that OTUD1 in hepatocytes affect TGF-β1 secretion by stabilizing HSP90β protein level, thereby promoting the activation of LX-2 cells. We identified HSP90β as a target of OTUD1 and propose OTUD1 as a potential therapeutic target for liver fibrosis.