[en] NF-kappaB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-kappaB2 processing into p52, a process defined as the alternative, or non-canonical, NF-kappaB 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 LTbetaR, is required for TNFalpha-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/LTbetaR-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-kappaB pathway.Cell Death and Differentiation advance online publication, 5 June 2015; doi:10.1038/cdd.2015.69.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Boutaffala, L.
Bertrand, M. J. M.
Remouchamps, Caroline ; Université de Liège > GIGA-R : Labo of Molecular Immunol. and Signal Transduction
Seleznik, G.
Reisinger, F.
Janas, M.
Benezech, C.
Fernandes, M. T.
Marchetti, S.
Mair, F.
Ganeff, C.
Hupalowska, A.
Ricci, J.-E.
Becher, B.
Piette, Jacques ; Université de Liège > Département des sciences de la vie > GIGA-R : Virologie - Immunologie
Knolle, P.
Caamano, J.
Vandenabeele, P.
Heikenwalder, M.
Dejardin, Emmanuel ; Université de Liège > GIGA-R : Labo of Molecular Immunol. and Signal Transduction
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