SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

Lingjie Yan, Tao Zhang, Kai Wang, Zezhao Chen, Yuanxin Yang, Bing Shan, Qi Sun, Mengmeng Zhang, Yichi Zhang, Yedan Zhong, Nan Liu, Jinyang Gu () and Daichao Xu ()
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Lingjie Yan: Chinese Academy of Sciences
Tao Zhang: Harvard Medical School
Kai Wang: Hangzhou First People’s Hospital Affiliated Zhejiang University School of Medicine
Zezhao Chen: Chinese Academy of Sciences
Yuanxin Yang: Chinese Academy of Sciences
Bing Shan: Chinese Academy of Sciences
Qi Sun: Chinese Academy of Sciences
Mengmeng Zhang: Chinese Academy of Sciences
Yichi Zhang: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yedan Zhong: Chinese Academy of Sciences
Nan Liu: Chinese Academy of Sciences
Jinyang Gu: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Daichao Xu: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34993-0

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