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

作者：Annibaldi Alessandro^*; John Sidonie Wicky; Berghe Tom Vanden; 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; Meier Pascal^*

来源：Molecular Cell, 2018, 69(4): 566-+.

DOI：10.1016/j.molcel.2018.01.027

Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor kappa B (NF-kappa B)-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.

• 出版日期2018-2-15