Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.

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Date
2018-02Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Animals
Mice, Inbred C57BL
Mice, Knockout
Humans
Mice
Protein-Serine-Threonine Kinases
MAP Kinase Kinase Kinases
Tumor Necrosis Factor-alpha
Intracellular Signaling Peptides and Proteins
NF-kappa B
Ubiquitin
Signal Transduction
Apoptosis
Inhibitor of Apoptosis Proteins
I-kappa B Kinase
Receptor-Interacting Protein Serine-Threonine Kinases
Ubiquitination
HEK293 Cells
Baculoviral IAP Repeat-Containing 3 Protein
Research team
Cell Death and Immunity
Language
eng
Date accepted
2018-01-19
License start date
2018-02
Citation
Molecular cell, 2018, 69 (4), pp. 566 - 580.e5
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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