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

Yong Tang, Hailin Tu, Jie Zhang, Xueqiang Zhao, Yini Wang, Jun Qin and Xin Lin ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12033-8

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