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The prevalence of TNFα-induced necrosis over apoptosis is determined by TAK1-RIP1 interplay

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Item Type:Article
Title:The prevalence of TNFα-induced necrosis over apoptosis is determined by TAK1-RIP1 interplay
Creators Name:Coel Arslan, S. and Scheidereit, C.
Abstract: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 TGF{beta}-activated Kinase-1 (TAK1) expression, catalytically active Receptor Interacting Protein 1 (RIP1)-dependent programmed necrosis overrides apoptotic processes following Tumor Necrosis Factor-{alpha} (TNF{alpha}) stimulation and results in rapid cell death. Importantly, the activation of the caspase cascade and caspase-8-mediated RIP1 cleavage in TNF{alpha}-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 TNF{alpha}-stimulated TNF-receptor I and also to inhibit the formation of TNF{alpha}-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.
Keywords:Apoptosis, Caspases, Gene Knockout Techniques, GTPase-Activating Proteins, MAP Kinase Kinase Kinases, Necrosis, NF-kappa B, Reactive Oxygen Species, Signal Transduction, Time Factors, Tumor Cell Line, Tumor Necrosis Factor-alpha, Ubiquitination, Animals, Mice
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e26069
Date:10 October 2011
Official Publication:https://doi.org/10.1371/journal.pone.0026069
PubMed:View item in PubMed

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