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Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2

  • Annibaldi, Alessandro
  • John, Sidonie Wicky
  • Vanden Berghe, Tom
  • Swatek, Kirby N
  • Ruan, Jianbin
  • Liccardi, Gianmaria
  • Bianchi, Katiuscia
  • Elliott, Paul R
  • Choi, Sze Men
  • Van Coillie, Samya
  • Bertin, John
  • Wu, Hao
  • Komander, David
  • Vandenabeele, Peter
  • Silke, John
  • Meier, Pascal
Publication Date
Jan 01, 2018
Ghent University Institutional Archive
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Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor kappa B (NF-kappa B)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains unclear whether ubiquitylation can directly repress TNF-induced death. Here, we show that ubiquitylation regulates RIPK1's cytotoxic potential not only via activation of downstream kinases and NF-kB transcriptional responses, but also by directly repressing RIPK1 kinase activity via ubiquitin-dependent inactivation. We find that the ubiquitin-associated (UBA) domain of cellular inhibitor of apoptosis (cIAP) 1 is required for optimal ubiquitin-lysine occupancy and K48 ubiquitylation of RIPK1. Independently of IKK and MK2, cIAP1-mediated and UBA-assisted ubiquitylation suppresses RIPK1 kinase auto-activation and, in addition, marks it for proteasomal degradation. In the absence of a functional UBA domain of cIAP1, more active RIPK1 kinase accumulates in response to TNF, causing RIPK1 kinase-mediated cell death and systemic inflammatory response syndrome. These results reveal a direct role for cIAP-mediated ubiquitylation in controlling RIPK1 kinase activity and preventing TNF-mediated cytotoxicity.

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