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Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation

Author

Listed:
  • Yves Dondelinger

    (VIB Center for Inflammation Research
    Ghent University)

  • Tom Delanghe

    (VIB Center for Inflammation Research
    Ghent University)

  • Dario Priem

    (VIB Center for Inflammation Research
    Ghent University)

  • Meghan A. Wynosky-Dolfi

    (University of Pennsylvania)

  • Daniel Sorobetea

    (University of Pennsylvania)

  • Diego Rojas-Rivera

    (VIB Center for Inflammation Research
    Ghent University
    Universidad Mayor)

  • Piero Giansanti

    (University of Utrecht
    Netherlands Proteomics Centre
    Technical University of Munich)

  • Ria Roelandt

    (VIB Center for Inflammation Research
    Ghent University)

  • Julia Gropengiesser

    (University Medical Center Eppendorf)

  • Klaus Ruckdeschel

    (University Medical Center Eppendorf)

  • Savvas N. Savvides

    (VIB Center for Inflammation Research
    Ghent University)

  • Albert J. R. Heck

    (University of Utrecht
    Netherlands Proteomics Centre)

  • Peter Vandenabeele

    (VIB Center for Inflammation Research
    Ghent University)

  • Igor E. Brodsky

    (University of Pennsylvania)

  • Mathieu J. M. Bertrand

    (VIB Center for Inflammation Research
    Ghent University)

Abstract

RIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09690-0
    DOI: 10.1038/s41467-019-09690-0
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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. 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.
    3. Remzi Onur Eren & Göksu Gökberk Kaya & Robin Schwarzer & Manolis Pasparakis, 2024. "IKKε and TBK1 prevent RIPK1 dependent and independent inflammation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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