NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
- The Inflammation Research Center IRC, VIB, DMBR, Ghent University, Ghent, Belgium.
- Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.
- Institute of Virology, Munich, Germany.
- Institute of Molecular Immunology and Technische Universität München (TUM)/Helmholtz Zentrum München (HMGU), Munich, Germany.
- School of Immunity and Infection, IBR-MRC, Centre for Immune Regulation, University of Birmingham, Birmingham, UK.
- INSERM U1065, Centre Méditéranéen de Médecine Moléculaire, Nice, France.
- Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland.
- Laboratory of Virology, GIGA-Research, University of Liège, Liège, Belgium.
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex. In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.
|Number of pages||14|
|Journal||Cell Death & Differentiation|
|Publication status||Published - Dec 2015|
- Animals, Apoptosis/drug effects, Caspase 8/chemistry, Cell Line, Fas-Associated Death Domain Protein/chemistry, GTPase-Activating Proteins/chemistry, HEK293 Cells, Humans, Inhibitor of Apoptosis Proteins/genetics, Liver/drug effects, Lymphotoxin beta Receptor/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B/metabolism, Phosphorylation, Protein-Serine-Threonine Kinases/deficiency, Receptors, Tumor Necrosis Factor, Type I/metabolism, Signal Transduction/drug effects, Thymus Gland/metabolism, Tumor Necrosis Factor-alpha/pharmacology