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Boutaffala, L.* ; Bertrand, M.J.* ; Remouchamps, C.* ; Seleznik, G.M.* ; 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.* ; Heikenwälder, M. ; Dejardin, E.*

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

Cell Death Differ. 22, 2020-2033 (2015)
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Quellenangaben Band: 22, Heft: 12, Seiten: 2020-2033 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Begutachtungsstatus Peer reviewed