title: TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation.
abstract: TNF activates three distinct intracellular signaling cascades leading to cell survival, caspase-8-mediated apoptosis, or receptor interacting protein kinase 3 (RIPK3)-dependent necrosis, also called necroptosis. Depending on the cellular context, one of these pathways is activated upon TNF challenge. When caspase-8 is activated, it drives the apoptosis cascade and blocks RIPK3-dependent necrosis. Here we report the biological event switching to activate necrosis over apoptosis. TAK1 kinase is normally transiently activated upon TNF stimulation. We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. In addition, we also demonstrated that activation of RIPK1 and RIPK3 promoted TAK1 activation, suggesting a positive feedforward loop of RIPK1, RIPK3, and TAK1. Conversely, ablation of TAK1 caused caspase-dependent apoptosis, in which Ripk3 deletion did not block cell death either in vivo or in vitro. Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis.
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695.
authors.forename: Sho
authors.initials: S
authors.lastname: Morioka
authors.forename: Peter
authors.initials: P
authors.lastname: Broglie
authors.forename: Emily
authors.initials: E
authors.lastname: Omori
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019426:Integrases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C498761:Tab2 protein, mouse; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C045073:Cre recombinase