NF-κB-Independent Role of IKKα/IKKβ in Preventing RIPK1 Kinase-Dependent Apoptotic and Necroptotic Cell Death during TNF Signaling.
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.
Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
Yves
Y
Dondelinger
Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
Sandrine
S
Jouan-Lanhouet
Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
Tatyana
T
Divert
Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, 4000 Liège, Belgium.
Emilie
E
Theatre
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
John
J
Bertin
Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
Peter J
PJ
Gough
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands.
Piero
P
Giansanti
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Centre for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, 3584 CH Utrecht, the Netherlands; Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands.
Albert J R
AJ
Heck
Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, 4000 Liège, Belgium.
Emmanuel
E
Dejardin
Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Methusalem Program, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium.
Peter
P
Vandenabeele
Inflammation Research Center, VIB, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, Zwijnaarde-Ghent 9052, Belgium. Electronic address: mathieu.bertrand@irc.vib-ugent.be.
Mathieu J M
MJ
Bertrand
D000818:Animals; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D051550:I-kappa B Kinase; C505526:Casp8 protein, mouse; D053181:Caspase 8