SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

• DOI: 10.1038/s41467-022-34993-0
• Publication Date: 2022-11-23T04:36:34Z
• Authors: Lingjie Yan; Tao Zhang; Kai Wang; Zezhao Chen; Yuanxin Yang; Bing Shan; Qi Sun; Mengmeng Zhang; Yichi Zhang; Yedan Zhong; Nan Liu; Jinyang Gu; Daichao Xu
• Keywords: Steatohepatitis; RIPK1

Activation of RIPK1-driven cell death and inflammation play important roles in the progression nonalcoholic steatohepatitis (NASH). However, mechanism underlying RIPK1 activation NASH remains unclear. Here we identified SENP1, a SUMO-specific protease, as key endogenous inhibitor RIPK1. SENP1 is progressively reduced proportion to severity patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes kinase-dependent manner. We demonstrate that deficiency sensitizes cells apoptosis by promoting following TNFα stimulation. Mechanistically, deSUMOylates TNF-R1 signaling complex (TNF-RSC), keeping check. Loss leads SUMOylation RIPK1, which re-orchestrates TNF-RSC modulates ubiquitination patterns activity Notably, genetic inhibition effectively reverses disease hepatocyte-specific male with high-fat-diet-induced fatty liver. propose deSUMOylation provides pathophysiologically relevant death-restricting checkpoint pathogenesis steatohepatitis.