NIK promotes tissue destruction independently of the alternative NF-[kappa]B pathway through TNFR1/RIP1-induced apoptosis

• Published in: Cell death and differentiation Vol. 22; no. 12; p. 2020
• Main Authors: Boutaffala, L, Bertrand, M J M, Remouchamps, C, Seleznik, G, Reisinger, F, Janas, M, Bénézech, C, Fernandes, M T, Marchetti, S, Mair, F, Ganeff, C, Hupalowska, A, Ricci, J-e, Becher, B, Piette, J, Knolle, P, Caamano, J, Vandenabeele, P, Heikenwalder, M, Dejardin, E
• Format: Journal Article
• Language: English
• Published: Rome Nature Publishing Group 01-12-2015
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.69

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.