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

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

In: Cell Death & Differentiation , Vol. 22, No. 12, 12.2015, p. 2020-33.

Research output: Contribution to journalArticlepeer-review

Harvard

Boutaffala, L, Bertrand, MJM, Remouchamps, C, Seleznik, G, Reisinger, F, Janas, M, Bénézech, C, Fernandes, MT, 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 2015, 'NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis', Cell Death & Differentiation , vol. 22, no. 12, pp. 2020-33. https://doi.org/10.1038/cdd.2015.69

APA

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. (2015). NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis. Cell Death & Differentiation , 22(12), 2020-33. https://doi.org/10.1038/cdd.2015.69

Vancouver

Author

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. / NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis. In: Cell Death & Differentiation . 2015 ; Vol. 22, No. 12. pp. 2020-33.

Bibtex

@article{4743538b6aea417db5291e54794fa237,
title = "NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis",
abstract = "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. ",
keywords = "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",
author = "L Boutaffala and Bertrand, {M J M} and C Remouchamps and G Seleznik and F Reisinger and M Janas and C B{\'e}n{\'e}zech and Fernandes, {M T} and S Marchetti and F Mair and C Ganeff and A Hupalowska and J-E Ricci and B Becher and J Piette and P Knolle and J Caamano and P Vandenabeele and M Heikenwalder and E Dejardin",
year = "2015",
month = dec,
doi = "10.1038/cdd.2015.69",
language = "English",
volume = "22",
pages = "2020--33",
journal = "Cell Death & Differentiation ",
issn = "1350-9047",
publisher = "Nature Publishing Group",
number = "12",

}

RIS

TY - JOUR

T1 - NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

AU - Boutaffala, L

AU - Bertrand, M J M

AU - Remouchamps, C

AU - Seleznik, G

AU - Reisinger, F

AU - Janas, M

AU - Bénézech, C

AU - Fernandes, M T

AU - Marchetti, S

AU - Mair, F

AU - Ganeff, C

AU - Hupalowska, A

AU - Ricci, J-E

AU - Becher, B

AU - Piette, J

AU - Knolle, P

AU - Caamano, J

AU - Vandenabeele, P

AU - Heikenwalder, M

AU - Dejardin, E

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis/drug effects

KW - Caspase 8/chemistry

KW - Cell Line

KW - Fas-Associated Death Domain Protein/chemistry

KW - GTPase-Activating Proteins/chemistry

KW - HEK293 Cells

KW - Humans

KW - Inhibitor of Apoptosis Proteins/genetics

KW - Liver/drug effects

KW - Lymphotoxin beta Receptor/metabolism

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - NF-kappa B/metabolism

KW - Phosphorylation

KW - Protein-Serine-Threonine Kinases/deficiency

KW - Receptors, Tumor Necrosis Factor, Type I/metabolism

KW - Signal Transduction/drug effects

KW - Thymus Gland/metabolism

KW - Tumor Necrosis Factor-alpha/pharmacology

U2 - 10.1038/cdd.2015.69

DO - 10.1038/cdd.2015.69

M3 - Article

C2 - 26045047

VL - 22

SP - 2020

EP - 2033

JO - Cell Death & Differentiation

JF - Cell Death & Differentiation

SN - 1350-9047

IS - 12

ER -