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

Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.
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Annibaldi A, Wicky John S, Vanden Berghe T, Swatek KN, Ruan J, Liccardi G, Bianchi K, Elliott PR, Choi SM, Van Coillie S, Bertin J, Wu H, Komander D, Vandenabeele P, Silke J, Meier P,


Annibaldi A, Wicky John S, Vanden Berghe T, Swatek KN, Ruan J, Liccardi G, Bianchi K, Elliott PR, Choi SM, Van Coillie S, Bertin J, Wu H, Komander D, Vandenabeele P, Silke J, Meier P, (click to view)

Annibaldi A, Wicky John S, Vanden Berghe T, Swatek KN, Ruan J, Liccardi G, Bianchi K, Elliott PR, Choi SM, Van Coillie S, Bertin J, Wu H, Komander D, Vandenabeele P, Silke J, Meier P,

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Molecular cell 69(4) 566-580.e5 pii 10.1016/j.molcel.2018.01.027

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.

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