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

ABSTRACT: NF-?B-inducing kinase (NIK) is well-known for its role in promoting p100/NF-?B2 processing into p52, a process defined as the alternative, or non-canonical, NF-?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?R, is required for TNF?-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?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-?B pathway.

SUBMITTER: Boutaffala L

PROVIDER: S-EPMC4816116 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

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

Cell death and differentiation 20150605 12

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 trigge ...[more]

PMID: 26045047

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Project description:A growing number of studies has shed light on the role of the NF-?? in non-small-cell lung cancer (NSCLC). To address the significance of major effectors of the NF-?? alternative pathway, we investigated the relationship between NF-??2, RelB, NIK and Bcl3 expression (mRNA and protein) and the clinical outcome of NSCLC patients. NF-??2, RelB, NIK and Bcl3 protein expression levels were assessed by immunohistochemistry in tissue samples from 151 NSCLC patients who had curative resection. mRNA levels were also evaluated in 69 patients using quantitative real-time PCR. Although all studied proteins were overexpressed in NSCLC (P?<?0.001 for all), only RelB mRNA levels were strongly increased in cancerous specimens compared to tumor-adjacent non-neoplastic tissues (P?=?0.009). Moreover, NF-?B2, RelB and Bcl3 expression was associated with overall survival (OS). In particular, cytoplasmic and mRNA expression of RelB was related to 5-year OS (P?=?0.014 and P?=?0.006, respectively). Multivariate analysis also showed that Bcl3 expression (nuclear and cytoplasmic) was associated with increased 5-year OS (P?=?0.002 and P?=?0.036, respectively). In addition, higher Bcl3 mRNA levels were associated with inferior OS in stages I & II and improved OS in stages III and IV after 5-year follow-up (P?=?0.004 and P?=?0.001, respectively). Furthermore, stage I patients with lower NF-?B2 mRNA levels had better 5-year survival in univariate and multivariate analysis (P?=?0.031 and P?=?0.028, respectively). Interestingly, RelB expression (cytoplasmic and mRNA) was inversely associated with relapse rates (P?=?0.027 and P?=?0.015, respectively), while low NIK cytoplasmic expression was associated with lower relapse rates (P?=?0.019). Cytoplasmic NIK expression as well as NF-?B2/ Bcl3 detection was associated with lymph node infiltration (P?=?0.039 and P?=?0.014, respectively). The present study confirms the deregulation of the NF-?B alternative pathway in NSCLC and also demonstrates the importance of this pathway in prognosis, recurrence and infiltration of regional lymph nodes.

Dataset Information

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

Publications

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

Similar Datasets

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