| First Author | Annibaldi A | Year | 2018 |
| Journal | Mol Cell | Volume | 69 |
| Issue | 4 | Pages | 566-580.e5 |
| PubMed ID | 29452637 | Mgi Jnum | J:260804 |
| Mgi Id | MGI:6150124 | Doi | 10.1016/j.molcel.2018.01.027 |
| Citation | Annibaldi A, et al. (2018) Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2. Mol Cell 69(4):566-580.e5 |
| abstractText | 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. |
