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SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

Author

Listed:
  • Lingjie Yan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Tao Zhang

    (Harvard Medical School)

  • Kai Wang

    (Hangzhou First People’s Hospital Affiliated Zhejiang University School of Medicine
    Zhejiang University)

  • Zezhao Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yuanxin Yang

    (Chinese Academy of Sciences
    University of 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
    Shanghai Key Laboratory of Aging Studies)

  • Jinyang Gu

    (Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
    Tongji Medical College, Huazhong University of Science and Technology)

  • Daichao Xu

    (Chinese Academy of Sciences
    Shanghai Key Laboratory of Aging Studies)

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.

Suggested Citation

  • 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, 2022. "SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34993-0
    DOI: 10.1038/s41467-022-34993-0
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    References listed on IDEAS

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    1. Cong Qiu & Yuewen Wang & Haige Zhao & Lingfeng Qin & Yanna Shi & Xiaolong Zhu & Lin Song & Xiaofei Zhou & Jian Chen & Hong Zhou & Haifeng Zhang & George Tellides & Wang Min & Luyang Yu, 2017. "The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
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    1. Jiang Ren & Shuai Wang & Zhi Zong & Ting Pan & Sijia Liu & Wei Mao & Huizhe Huang & Xiaohua Yan & Bing Yang & Xin He & Fangfang Zhou & Long Zhang, 2024. "TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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