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RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis

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  • Jingchun Du

    (University of Texas Southwestern Medical Center
    Guangzhou Medical University)

  • Yougui Xiang

    (University of Texas Southwestern Medical Center
    Caris Life Sciences)

  • Hua Liu

    (University of Texas Southwestern Medical Center
    Jiangxi University of Chinese Medicine)

  • Shuzhen Liu

    (University of Texas Southwestern Medical Center)

  • Ashwani Kumar

    (University of Texas Southwestern Medical Center)

  • Chao Xing

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Zhigao Wang

    (University of Texas Southwestern Medical Center
    University of South Florida)

Abstract

Receptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole-genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and type I necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1γ) to complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1γ fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g−/− mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27367-5
    DOI: 10.1038/s41467-021-27367-5
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    References listed on IDEAS

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    1. Chen Wang & Li Deng & Mei Hong & Giridhar R. Akkaraju & Jun-ichiro Inoue & Zhijian J. Chen, 2001. "TAK1 is a ubiquitin-dependent kinase of MKK and IKK," Nature, Nature, vol. 412(6844), pages 346-351, July.
    2. Yves Dondelinger & Tom Delanghe & Dario Priem & Meghan A. Wynosky-Dolfi & Daniel Sorobetea & Diego Rojas-Rivera & Piero Giansanti & Ria Roelandt & Julia Gropengiesser & Klaus Ruckdeschel & Savvas N. S, 2019. "Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    3. Lucie Laurien & Masahiro Nagata & Hannah Schünke & Tom Delanghe & Janica L. Wiederstein & Snehlata Kumari & Robin Schwarzer & Teresa Corona & Marcus Krüger & Mathieu J. M. Bertrand & Vangelis Kondylis, 2020. "Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    4. Najoua Lalaoui & Steven E. Boyden & Hirotsugu Oda & Geryl M. Wood & Deborah L. Stone & Diep Chau & Lin Liu & Monique Stoffels & Tobias Kratina & Kate E. Lawlor & Kristien J. M. Zaal & Patrycja M. Hoff, 2020. "Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease," Nature, Nature, vol. 577(7788), pages 103-108, January.
    5. Yingying Zhang & Sheng Sean Su & Shubo Zhao & Zhentao Yang & Chuan-Qi Zhong & Xin Chen & Qixu Cai & Zhang-Hua Yang & Deli Huang & Rui Wu & Jiahuai Han, 2017. "RIP1 autophosphorylation is promoted by mitochondrial ROS and is essential for RIP3 recruitment into necrosome," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    6. 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.
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