RESUMO
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 LTßR, 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/LTßR-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.
Assuntos
Proteínas Ativadoras de GTPase/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 8/química , Caspase 8/metabolismo , Linhagem Celular , Proteína de Domínio de Morte Associada a Fas/química , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteínas Ativadoras de GTPase/química , Células HEK293 , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Receptor beta de Linfotoxina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Timo/metabolismo , Timo/patologia , Fator de Necrose Tumoral alfa/farmacologia , Quinase Induzida por NF-kappaBRESUMO
The authors draw attention to vacuum mattresses which are a modern appliance for the immobilization of casualties and patients. They present their initial experience with the use of these mattresses during examinations on a computed tomograph, during all-body stereotaxis and minor surgical operations. The material from which the mattress is made allows X-rays to penetrate, therefore it can be used also for immobilization of restless patients and children during X-ray examinations. It is, however, possible to manufacture also various types of vacuum splints for fixation of the extremities after injuries.