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Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis

Author

Listed:
  • Jiefei Geng

    (Harvard Medical School)

  • Yasushi Ito

    (Harvard Medical School)

  • Linyu Shi

    (Chinese Academy of Sciences)

  • Palak Amin

    (Harvard Medical School)

  • Jiachen Chu

    (Harvard Medical School)

  • Amanda Tomie Ouchida

    (Harvard Medical School)

  • Adnan Kasim Mookhtiar

    (Harvard Medical School)

  • Heng Zhao

    (Harvard Medical School)

  • Daichao Xu

    (Harvard Medical School)

  • Bing Shan

    (Chinese Academy of Sciences)

  • Ayaz Najafov

    (Harvard Medical School)

  • Guangping Gao

    (University of Massachusetts Medical School)

  • Shizuo Akira

    (WPI Immunology Frontier Research Center (IFReC), Osaka University)

  • Junying Yuan

    (Harvard Medical School
    Chinese Academy of Sciences)

Abstract

Stimulation of TNFR1 by TNFα can promote three distinct alternative mechanisms of cell death: necroptosis, RIPK1-independent and -dependent apoptosis. How cells decide which way to die is unclear. Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision. Using phospho-Ser321 as a marker, we show that the transient phosphorylation of RIPK1 intermediate domain induced by TNFα leads to RIPK1-independent apoptosis when NF-κB activation is inhibited by cycloheximide. On the other hand, blocking Ser321 phosphorylation promotes RIPK1 activation and its interaction with FADD to mediate RIPK1-dependent apoptosis (RDA). Finally, sustained phosphorylation of RIPK1 intermediate domain at multiple sites by TAK1 promotes its interaction with RIPK3 and necroptosis. Thus, absent, transient and sustained levels of TAK1-mediated RIPK1 phosphorylation may represent distinct states in TNF-RSC to dictate the activation of three alternative cell death mechanisms, RDA, RIPK1-independent apoptosis and necroptosis.

Suggested Citation

  • Jiefei Geng & Yasushi Ito & Linyu Shi & Palak Amin & Jiachen Chu & Amanda Tomie Ouchida & Adnan Kasim Mookhtiar & Heng Zhao & Daichao Xu & Bing Shan & Ayaz Najafov & Guangping Gao & Shizuo Akira & Jun, 2017. "Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00406-w
    DOI: 10.1038/s41467-017-00406-w
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    Cited by:

    1. Hailin Tu & Weihang Xiong & Jie Zhang & Xueqiang Zhao & Xin Lin, 2022. "Tyrosine phosphorylation regulates RIPK1 activity to limit cell death and inflammation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Tao Zhang & Na Zhang & Jing Xing & Shuhua Zhang & Yulu Chen & Daichao Xu & Jinyang Gu, 2023. "UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Jingchun Du & Yougui Xiang & Hua Liu & Shuzhen Liu & Ashwani Kumar & Chao Xing & Zhigao Wang, 2021. "RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. 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.

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