NF-κB-Independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-Dependent Apoptotic and Necroptotic Cell Death during TNF Signaling
Autor: | Dondelinger, Yves, Jouan-Lanhouet, Sandrine, Divert, Tatyana, Theatre, Emilie, Bertin, John, Gough, Peter J, Giansanti, Piero, Heck, Albert J R, Dejardin, Emmanuel, Vandenabeele, Peter, Bertrand, Mathieu J M, Sub Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics |
---|---|
Přispěvatelé: | Sub Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics |
Jazyk: | angličtina |
Rok vydání: | 2015 |
Předmět: |
Programmed cell death
medicine.medical_treatment Necroptosis Fas-Associated Death Domain Protein Biology Caspase 8 Cell Line RIPK1 chemistry.chemical_compound Mice medicine Animals Phosphorylation Molecular Biology Cell Death Tumor Necrosis Factor-alpha NF-kappa B NF-κB Cell Biology Fibroblasts Embryo Mammalian Cell biology I-kappa B Kinase Cytokine chemistry Apoptosis Receptors Tumor Necrosis Factor Type I Receptor-Interacting Protein Serine-Threonine Kinases Cancer research Signal transduction Signal Transduction |
Zdroj: | Molecular Cell. Cell Press |
ISSN: | 1097-2765 |
Popis: | 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-κB-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-κB activation. We provide in vitro and in vivo evidence that inhibition of IKKα/IKKβ or its upstream activators sensitizes cells to death by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We therefore report on an unexpected, NF-κB-independent role for the IKK complex in protecting cells from RIPK1-dependent death downstream of TNFR1. |
Databáze: | OpenAIRE |
Externí odkaz: |