1. Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2
- Author
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Annibaldi, Alessandro, John, Sidonie Wicky, Vanden Berghe, Tom, Swatek, Kirby N, Ruan, Jianbin, Liccardi, Gianmaria, Bianchi, Katiuscia, Elliott, Paul R, Choi, Sze Men, Van Coillie, Samya, Bertin, John, Wu, Hao, Komander, David, Vandenabeele, Peter, Silke, John, and Meier, Pascal
- Subjects
DOMAINS ,RIPK1 ,NF-KAPPA-B ,TNF ,necroptosis ,Apoptosis ,Protein Serine-Threonine Kinases ,CHAIN ASSEMBLY COMPLEX ,Article ,caspase-8 ,Inhibitor of Apoptosis Proteins ,ACTIVATION ,Mice ,INFLAMMATION ,BINDING ,ubiquitin ,Medicine and Health Sciences ,Animals ,Humans ,Mice, Knockout ,Tumor Necrosis Factor-alpha ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,Ubiquitination ,Biology and Life Sciences ,MAP Kinase Kinase Kinases ,TNF-ALPHA ,CANCER ,Baculoviral IAP Repeat-Containing 3 Protein ,APOPTOSIS ,I-kappa B Kinase ,Mice, Inbred C57BL ,cell death ,HEK293 Cells ,CELL-DEATH ,inflammation ,Receptor-Interacting Protein Serine-Threonine Kinases ,cIAPs ,SURVIVAL ,Signal Transduction - Abstract
Summary 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., Graphical Abstract, Highlights • Ubiquitylation directly controls RIPK1 kinase activity in TNF signaling • UBA-dependent ubiquitylation of RIPK1 represses its kinase activity and cell death • The UBA contributes to optimal occupancy of ubiquitin-acceptor lysines in RIPK1 • UBA-dependent ubiquitylation of RIPK1 also targets it for proteasomal degradation, Annibaldi et al. show that cIAP-mediated ubiquitylation of RIPK1 kinase suppresses its auto-activation and, in addition, marks it for proteasomal degradation. These results reveal a direct role for ubiquitin in controlling RIPK1 kinase activity and suppressing TNF-mediated cytotoxicity.
- Published
- 2018