NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

L Boutaffala, M J M Bertrand, C Remouchamps, G Seleznik, F Reisinger, M Janas, C Bénézech, M T Fernandes, S Marchetti, F Mair, C Ganeff, A Hupalowska, J-E Ricci, B Becher, J Piette, P Knolle, J Caamano, P Vandenabeele, M Heikenwalder, E Dejardin

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2020-2033
Number of pages14
JournalCell Death & Differentiation
Issue number12
Early online date5 Jun 2015
Publication statusPublished - 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


Dive into the research topics of 'NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis'. Together they form a unique fingerprint.

Cite this