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

Alessandro Annibaldi, Sidonie Wicky John, Tom Vanden Berghe (UGent) , Kirby N Swatek, Jianbin Ruan, Gianmaria Liccardi, Katiuscia Bianchi, Paul R Elliott, Sze Men Choi (UGent) , Samya Van Coillie (UGent) , et al.
(2018) MOLECULAR CELL. 69(4). p.566-580
Author
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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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MLA
Annibaldi, Alessandro, et al. “Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.” MOLECULAR CELL, vol. 69, no. 4, 2018, pp. 566–80, doi:10.1016/j.molcel.2018.01.027.
APA
Annibaldi, A., John, S. W., Vanden Berghe, T., Swatek, K. N., Ruan, J., Liccardi, G., … Meier, P. (2018). Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2. MOLECULAR CELL, 69(4), 566–580. https://doi.org/10.1016/j.molcel.2018.01.027
Chicago author-date
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): 566–80. https://doi.org/10.1016/j.molcel.2018.01.027.
Chicago author-date (all authors)
Annibaldi, Alessandro, Sidonie Wicky John, Tom Vanden Berghe, Kirby N Swatek, Jianbin Ruan, Gianmaria Liccardi, Katiuscia Bianchi, Paul R Elliott, Sze Men Choi, Samya Van Coillie, John Bertin, Hao Wu, David Komander, Peter Vandenabeele, John Silke, and Pascal Meier. 2018. “Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.” MOLECULAR CELL 69 (4): 566–580. doi:10.1016/j.molcel.2018.01.027.
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.
IEEE
[1]
A. Annibaldi et al., “Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2,” MOLECULAR CELL, vol. 69, no. 4, pp. 566–580, 2018.
@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}},
  keywords     = {{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://doi.org/10.1016/j.molcel.2018.01.027}},
  volume       = {{69}},
  year         = {{2018}},
}
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