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K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation

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  • Yong Tang

    (Tsinghua University-Peking University Jointed Center for Life Sciences)

  • Hailin Tu

    (Tsinghua University-Peking University Jointed Center for Life Sciences)

  • Jie Zhang

    (Tsinghua University-Peking University Jointed Center for Life Sciences)

  • Xueqiang Zhao

    (Tsinghua University-Peking University Jointed Center for Life Sciences)

  • Yini Wang

    (Institute of Lifeomics)

  • Jun Qin

    (Institute of Lifeomics)

  • Xin Lin

    (Tsinghua University-Peking University Jointed Center for Life Sciences)

Abstract

Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity. However, how its kinase activity is regulated remains poorly understood. Here, we generate Ripk1K376R/K376R knock-in mice in which the Lys(K)63-linked ubiquitination of RIPK1 is impaired. The knock-in mice display an early embryonic lethality due to massive cell death that is resulted from reduced TAK1-mediated suppression on RIPK1 kinase activity and forming more TNFR1 complex II in Ripk1K376R/K376R cells in response to TNFα. Although TNFR1 deficiency delays the lethality, concomitant deletion of RIPK3 and Caspase8 fully prevents embryonic lethality of Ripk1K376R/K376R mice. Notably, Ripk1K376R/- mice are viable but develop severe systemic inflammation that is mainly driven by RIPK3-dependent signaling pathway, indicating that K63-linked ubiquitination on Lys376 residue of RIPK1 also contributes to inflammation process. Together, our study reveals the mechanism by which K63-linked ubiquitination on K376 regulates RIPK1 kinase activity to control cell death programs.

Suggested Citation

  • Yong Tang & Hailin Tu & Jie Zhang & Xueqiang Zhao & Yini Wang & Jun Qin & Xin Lin, 2019. "K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell death during embryogenesis and inflammation," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12033-8
    DOI: 10.1038/s41467-019-12033-8
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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.

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