Journal article
Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2
A Annibaldi, S Wicky John, T Vanden Berghe, KN Swatek, J Ruan, G Liccardi, K Bianchi, PR Elliott, SM Choi, S Van Coillie, J Bertin, H Wu, D Komander, P Vandenabeele, J Silke, P Meier
Molecular Cell | CELL PRESS | Published : 2018
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 ubiqui..
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Awarded by Lister Institute of Preventive Medicine
Funding Acknowledgements
We would like to thank Afshan McCarthy, Alan Ashworth, Chris Lord, Henning Walczak, Shaomeng Wang, Lynn Wong, and Rachael Klevit for support, reagents, and advice. We also thank members of the Meier, Silke, and Komander laboratories for helpful discussions. We would like to apologize to the many authors whose work we could not cite due to space restrictions. A. A. is supported by a fellowship from the Swiss National Foundation (PBLAP3_142759 and P300P3_147867). Work in the Meier lab is funded by Breast Cancer Now (CTR-QR14-007), Medical Research Council (MRC) (MR/M019217/1), and Komen Promise (PG12220321). Work in the D.K. lab is funded by MRC (U105192732), the European Research Council (724804), and the Lister Institute of Preventive Medicine. J.S. is supported by an NHMRC fellowship (753300). We acknowledge NHS funding to the NIHR Biomedical Research Centre.