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Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2

(2018) MOLECULAR CELL. 69(4). p.566-580
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Abstract
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.
Keywords
NF-KAPPA-B, CHAIN ASSEMBLY COMPLEX, CELL-DEATH, TNF-ALPHA, BINDING, DOMAINS, INFLAMMATION, ACTIVATION, APOPTOSIS, SURVIVAL, CANCER

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Chicago
Annibaldi, Alessandro, Sidonie Wicky John, Tom Vanden Berghe, Kirby N Swatek, Jianbin Ruan, Gianmaria Liccardi, Katiuscia Bianchi, et al. 2018. “Ubiquitin-mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.” Molecular Cell 69 (4): 566–580.
APA
Annibaldi, A., John, S. W., Vanden Berghe, T., Swatek, K. N., Ruan, J., Liccardi, G., Bianchi, K., et al. (2018). Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2. MOLECULAR CELL, 69(4), 566–580.
Vancouver
1.
Annibaldi A, John SW, Vanden Berghe T, Swatek KN, Ruan J, Liccardi G, et al. Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2. MOLECULAR CELL. 2018;69(4):566–80.
MLA
Annibaldi, Alessandro, Sidonie Wicky John, Tom Vanden Berghe, et al. “Ubiquitin-mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.” MOLECULAR CELL 69.4 (2018): 566–580. Print.
@article{8554311,
  abstract     = {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.},
  author       = {Annibaldi, Alessandro and John, Sidonie Wicky and Vanden Berghe, Tom and Swatek, Kirby N and Ruan, Jianbin and Liccardi, Gianmaria and Bianchi, Katiuscia and Elliott, Paul R and Choi, Sze Men and Van Coillie, Samya and Bertin, John and Wu, Hao and Komander, David and Vandenabeele, Peter and Silke, John and Meier, Pascal},
  issn         = {1097-2765},
  journal      = {MOLECULAR CELL},
  keyword      = {NF-KAPPA-B,CHAIN ASSEMBLY COMPLEX,CELL-DEATH,TNF-ALPHA,BINDING,DOMAINS,INFLAMMATION,ACTIVATION,APOPTOSIS,SURVIVAL,CANCER},
  language     = {eng},
  number       = {4},
  pages        = {566--580},
  title        = {Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2},
  url          = {http://dx.doi.org/10.1016/j.molcel.2018.01.027},
  volume       = {69},
  year         = {2018},
}

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