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NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling

(2015) MOLECULAR CELL. 60(1). p.63-76
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
TNF is a master pro-inflammatory cytokine. Activation of TNFR1 by TNF can result in both RIPK1-independent apoptosis and RIPK1 kinase-dependent apoptosis or necroptosis. These cell death outcomes are regulated by two distinct checkpoints during TNFR1 signaling. TNF-mediated NF-kappa B-dependent induction of pro-survival or anti-apoptotic molecules is a well-known late checkpoint in the pathway, protecting cells from RIPK1-independent death. On the other hand, the molecular mechanism regulating the contribution of RIPK1 to cell death is far less understood. We demonstrate here that the IKK complex phosphorylates RIPK1 at TNFR1 complex I and protects cells from RIPK1 kinase-dependent death, independent of its function in NF-kappa B activation. We provide in vitro and in vivo evidence that inhibition of IKK alpha/IKK beta or its upstream activators sensitizes cells to death by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We therefore report on an unexpected, NF-kappa B-independent role for the IKK complex in protecting cells from RIPK1-dependent death downstream of TNFR1.
Keywords
DOMAIN-LIKE, PROGRAMMED NECROSIS, RECEPTOR 1, CASPASE-8 ACTIVATION, DEFICIENT MICE, NEMO/IKK-GAMMA, MICE LACKING, MIXED LINEAGE KINASE, SEVERE LIVER DEGENERATION, SMALL-MOLECULE INHIBITOR

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Citation

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MLA
Dondelinger, Yves et al. “NF-κB-independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-dependent Apoptotic and Necroptotic Cell Death During TNF Signaling.” MOLECULAR CELL 60.1 (2015): 63–76. Print.
APA
Dondelinger, Y., Jouan-Lanhouet, S., Divert, T., Theatre, E., Bertin, J., Gough, P. J., Giansanti, P., et al. (2015). NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. MOLECULAR CELL, 60(1), 63–76.
Chicago author-date
Dondelinger, Yves, Sandrine Jouan-Lanhouet, Tatyana Divert, Emilie Theatre, John Bertin, Peter J Gough, Piero Giansanti, et al. 2015. “NF-κB-independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-dependent Apoptotic and Necroptotic Cell Death During TNF Signaling.” Molecular Cell 60 (1): 63–76.
Chicago author-date (all authors)
Dondelinger, Yves, Sandrine Jouan-Lanhouet, Tatyana Divert, Emilie Theatre, John Bertin, Peter J Gough, Piero Giansanti, Albert JR Heck, Emmanuel Dejardin, Peter Vandenabeele, and Mathieu Bertrand. 2015. “NF-κB-independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-dependent Apoptotic and Necroptotic Cell Death During TNF Signaling.” Molecular Cell 60 (1): 63–76.
Vancouver
1.
Dondelinger Y, Jouan-Lanhouet S, Divert T, Theatre E, Bertin J, Gough PJ, et al. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. MOLECULAR CELL. 2015;60(1):63–76.
IEEE
[1]
Y. Dondelinger et al., “NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling,” MOLECULAR CELL, vol. 60, no. 1, pp. 63–76, 2015.
@article{6971087,
  abstract     = {TNF is a master pro-inflammatory cytokine. Activation of TNFR1 by TNF can result in both RIPK1-independent apoptosis and RIPK1 kinase-dependent apoptosis or necroptosis. These cell death outcomes are regulated by two distinct checkpoints during TNFR1 signaling. TNF-mediated NF-kappa B-dependent induction of pro-survival or anti-apoptotic molecules is a well-known late checkpoint in the pathway, protecting cells from RIPK1-independent death. On the other hand, the molecular mechanism regulating the contribution of RIPK1 to cell death is far less understood. We demonstrate here that the IKK complex phosphorylates RIPK1 at TNFR1 complex I and protects cells from RIPK1 kinase-dependent death, independent of its function in NF-kappa B activation. We provide in vitro and in vivo evidence that inhibition of IKK alpha/IKK beta or its upstream activators sensitizes cells to death by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We therefore report on an unexpected, NF-kappa B-independent role for the IKK complex in protecting cells from RIPK1-dependent death downstream of TNFR1.},
  author       = {Dondelinger, Yves and Jouan-Lanhouet, Sandrine and Divert, Tatyana and Theatre, Emilie and Bertin, John and Gough, Peter J and Giansanti, Piero and Heck, Albert JR and Dejardin, Emmanuel and Vandenabeele, Peter and Bertrand, Mathieu},
  issn         = {1097-2765},
  journal      = {MOLECULAR CELL},
  keywords     = {DOMAIN-LIKE,PROGRAMMED NECROSIS,RECEPTOR 1,CASPASE-8 ACTIVATION,DEFICIENT MICE,NEMO/IKK-GAMMA,MICE LACKING,MIXED LINEAGE KINASE,SEVERE LIVER DEGENERATION,SMALL-MOLECULE INHIBITOR},
  language     = {eng},
  number       = {1},
  pages        = {63--76},
  title        = {NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling},
  url          = {http://dx.doi.org/10.1016/j.molcel.2015.07.032},
  volume       = {60},
  year         = {2015},
}

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