Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2
- Author(s)
- 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, J; Meier, P;
- Details
- Publication Year 2018-02-15,Volume 69,Issue #4,Page 566-580 e5
- Journal Title
- Mol Cell
- Publication Type
- Journal Article
- Abstract
- Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor kappaB (NF-kappaB)-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.
- Publisher
- Cell Press
- Research Division(s)
- Cell Signalling And Cell Death
- PubMed ID
- 29452637
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2018.01.027
- Open Access at Publisher's Site
https://doi.org/10.1016/j.molcel.2018.01.027- NHMRC Grants
- NHMRC/753300,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-02-28 10:12:09
Last Modified: 2018-02-28 11:29:42