SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

• Published in: Nature communications 2022-11, Vol.13 (1), p.7153-7153, Article 7153
• Main Authors: Yan, Lingjie, Zhang, Tao, Wang, Kai, Chen, Zezhao, Yang, Yuanxin, Shan, Bing, Sun, Qi, Zhang, Mengmeng, Zhang, Yichi, Zhong, Yedan, Liu, Nan, Gu, Jinyang, Xu, Daichao
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/21; 13/51; 13/89; 13/95; 14/19; 38/39; 38/77; 38/90; 45/91; 631/80/458/538; 631/80/82/23; 64/110; 64/60; 692/699/317; 82/58; 82/83; 96/63; Animals; Apoptosis; Cell activation; Cell death; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Fatty liver; Hepatocytes - metabolism; High fat diet; Humanities and Social Sciences; Inflammation; Inflammation - pathology; Kinases; Liver; Liver diseases; Male; Mice; Mice, Knockout; Mortality; multidisciplinary; Non-alcoholic Fatty Liver Disease - metabolism; Pathogenesis; Phenotypes; Phosphotransferases - metabolism; Protease; Proteinase; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Science; Science (multidisciplinary); SUMO protein; Tumor necrosis factor-α; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34993-0

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