title: NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis.
abstract: 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.
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Boutaffala
authors.affiliation: The Inflammation Research Center IRC, VIB, DMBR, Ghent University, Ghent, Belgium.
authors.forename: M J M
authors.initials: MJ
authors.lastname: Bertrand
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Remouchamps
authors.affiliation: Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Seleznik
authors.affiliation: Institute of Virology, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Reisinger
authors.affiliation: Institute of Molecular Immunology and Technische Universität München (TUM)/Helmholtz Zentrum München (HMGU), Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Janas
authors.affiliation: School of Immunity and Infection, IBR-MRC, Centre for Immune Regulation, University of Birmingham, Birmingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bénézech
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: M T
authors.initials: MT
authors.lastname: Fernandes
authors.affiliation: INSERM U1065, Centre Méditéranéen de Médecine Moléculaire, Nice, France.
authors.forename: S
authors.initials: S
authors.lastname: Marchetti
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Mair
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Ganeff
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Hupalowska
authors.affiliation: INSERM U1065, Centre Méditéranéen de Médecine Moléculaire, Nice, France.
authors.forename: J-E
authors.initials: JE
authors.lastname: Ricci
authors.affiliation: Institute of Experimental Immunology, University of Zurich, Zürich, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Becher
authors.affiliation: Laboratory of Virology, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Piette
authors.affiliation: Institute of Molecular Immunology and Technische Universität München (TUM)/Helmholtz Zentrum München (HMGU), Munich, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Knolle
authors.affiliation: School of Immunity and Infection, IBR-MRC, Centre for Immune Regulation, University of Birmingham, Birmingham, UK.
authors.forename: J
authors.identifier: http://orcid.org/0000-0003-3530-7056
authors.initials: J
authors.lastname: Caamano
authors.affiliation: The Inflammation Research Center IRC, VIB, DMBR, Ghent University, Ghent, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Institute of Virology, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Laboratory of Molecular Immunology and Signal Transduction, GIGA-Research, University of Liège, Liège, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Dejardin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D053181:Caspase 8; D053200:Fas-Associated Death Domain Protein; D020690:GTPase-Activating Proteins; D051034:Inhibitor of Apoptosis Proteins; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000097782:NF-kappaB-Inducing Kinase; C505534:Fadd protein, mouse; C490620:Ralbp1 protein, mouse