The prevalence of TNFα-induced necrosis over apoptosis is determined by TAK1-RIP1 interplay.
Death receptor-induced programmed necrosis is regarded as a secondary death mechanism dominating only in cells that cannot properly induce caspase-dependent apoptosis. Here, we show that in cells lacking TGFβ-activated Kinase-1 (TAK1) expression, catalytically active Receptor Interacting Protein 1 (RIP1)-dependent programmed necrosis overrides apoptotic processes following Tumor Necrosis Factor-α (TNFα) stimulation and results in rapid cell death. Importantly, the activation of the caspase cascade and caspase-8-mediated RIP1 cleavage in TNFα-stimulated TAK1 deficient cells is not sufficient to prevent RIP1-dependent necrosome formation and subsequent programmed necrosis. Our results demonstrate that TAK1 acts independently of its kinase activity to prevent the premature dissociation of ubiquitinated-RIP1 from TNFα-stimulated TNF-receptor I and also to inhibit the formation of TNFα-induced necrosome complex consisting of RIP1, RIP3, FADD, caspase-8 and cFLIP(L). The surprising prevalence of catalytically active RIP1-dependent programmed necrosis over apoptosis despite ongoing caspase activity implicates a complex regulatory mechanism governing the decision between both cell death pathways following death receptor stimulation.
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Seda Çöl
SÇ
Arslan
Claus
C
Scheidereit
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
D020169:Caspases; D020690:GTPase-Activating Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C490620:Ralbp1 protein, mouse