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Mol Cell. 2018 Feb 15;69(4):566-580.e5. doi: 10.1016/j.molcel.2018.01.027.

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

Author information

1
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. Electronic address: alessandro.annibaldi@icr.ac.uk.
2
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
3
VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
4
Medical Research Council, Laboratory of Molecular Biology, Cambridge, UK.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Room 3024B, 3 Blackfan Circle, Boston, MA 02115, USA.
6
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK; Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
7
Pattern Recognition Receptor DPU and Platform Technology and Science, GlaxoSmithKline, Collegeville Road, Collegeville, PA 19426, USA.
8
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
9
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. Electronic address: pmeier@icr.ac.uk.

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.

KEYWORDS:

RIPK1; TNF; apoptosis; cIAPs; caspase-8; cell death; inflammation; necroptosis; ubiquitin

PMID:
29452637
PMCID:
PMC5823975
DOI:
10.1016/j.molcel.2018.01.027
[Indexed for MEDLINE]
Free PMC Article

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