Journal
CELL DEATH AND DIFFERENTIATION
Volume 22, Issue 12, Pages 2020-2033Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2015.69
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Funding
- Belgian grants from the 'Fondation belge Contre le Cancer, FCC'
- Plan Cancer Action 29, from the Televie and from the Centre Anticancereux of the University of Liege (Belgium)
- Swiss National Foundations (SNF)
- Helmholtz foundation
- ERC Starting grant
- Peter Hans Hofschneider foundation
- Stiftung experimentelle Biomedizin (Peter Hans Hofschneider Stiftung)
- PCCC (preclinical comprehensive cancer center)
- European Union FP7 (INFLA-CARE)
- BBSRC
- European grant (Euregional PACT II) from the Flemish Government
- Methusalem grant from the Flemish Government [BOF09/01M00709]
- Federal grant from the Belgian government (Interuniversity Attraction Poles) [IAP7/32]
- Televie (Belgium)
- Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/75137/2010]
- BBSRC [BB/K009400/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/K009400/1] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/75137/2010] Funding Source: FCT
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NF-kappa B-inducing kinase (NIK) is well-known for its role in promoting p100/NF-kappa B2 processing into p52, a process defined as the alternative, or non-canonical, NF-kappa B 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 LT beta R, is required for TNF alpha-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/LT beta R-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-kappa B pathway.
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