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.
Highlights
Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity
These data suggest that Ripk1K376R/K376R mice died around E13.5 resulted from excessive cell death and severe inflammation
Since K63-linked ubiquitination of RIPK1 in Complex I can function as docking sites for the recruitment of NEMO and tumor growth factor-β-activated kinase 1 (TAK1) to further induce nuclear factor-κB (NF-κB) activation, we examined the formation of Complex I, and found that Ripk1K376R/K376R mutation significantly decreased the recruitment of NEMO, A20, TAK1, and
Summary
Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of cell death through its kinase activity. 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. Receptor-interacting protein kinase 1 (RIPK1) is a serine/ threonine kinase that plays a critical role in various immune signaling pathways to regulate cell survival or cell death[1]. Inhibition of IKKα/β could enhance RIPK1 kinase activity to promote Complex II formation[10]. K63-linked ubiquitination of RIPK1 is required for tumor necrosis factor-α (TNFα)-induced NF-κB activation, and inhibits cell death[19,20,21]. Linear ubiquitin chain assembly complex (LUBAC) can conjugate Met1-linked ubiquitination chains to RIPK1 to promote NF-κB activation[22,23]. A recent study reported that ABIN-1 regulated RIPK1 activation by linking Met1-linked ubiquitination with K63-linked deubiquitination, suggesting a crosstalk between different ubiquitination chains on the regulation of RIPK1 activation[31]
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