Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2
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
WEHI Research Division(s)
Cell Signalling And Cell Death
PubMed ID
29452637
Open Access at Publisher's Site
https://doi.org/10.1016/j.molcel.2018.01.027
NHMRC Grants
NHMRC/753300
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
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