Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2 Academic Article uri icon

abstract

  • Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-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.

authors

  • Annibaldi, A
  • Wicky John, S
  • Vanden Berghe, T
  • Swatek, KN
  • Ruan, J
  • Liccardi, G
  • Bianchi, K
  • Elliott, PR
  • Choi, SM
  • Van Coillie, S
  • Bertin, J
  • Wu, H
  • Komander, D
  • Vandenabeele, P
  • Silke, John
  • Meier, P

publication date

  • 2018

has subject area