title: Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis.
abstract: Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 trigger pro-inflammatory cell death termed "necroptosis." Studies with RIPK3-deficient mice or the RIPK1 inhibitor necrostatin-1 suggest that necroptosis exacerbates pathology in many disease models. We engineered mice expressing catalytically inactive RIPK3 D161N or RIPK1 D138N to determine the need for the active kinase in the whole animal. Unexpectedly, RIPK3 D161N promoted lethal RIPK1- and caspase-8-dependent apoptosis. In contrast, mice expressing RIPK1 D138N were viable and, like RIPK3-deficient mice, resistant to tumor necrosis factor (TNF)-induced hypothermia. Cells expressing RIPK1 D138N were resistant to TNF-induced necroptosis, whereas TNF-induced signaling pathways promoting gene transcription were unperturbed. Our data indicate that the kinase activity of RIPK3 is essential for necroptosis but also governs whether a cell activates caspase-8 and dies by apoptosis.
authors.affiliation: Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Newton
authors.forename: Debra L
authors.initials: DL
authors.lastname: Dugger
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Wickliffe
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kapoor
authors.forename: M Cristina
authors.initials: MC
authors.lastname: de Almagro
authors.forename: Domagoj
authors.initials: D
authors.lastname: Vucic
authors.forename: Laszlo
authors.initials: L
authors.lastname: Komuves
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Ferrando
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: Joshua
authors.initials: J
authors.lastname: Webster
authors.forename: Merone
authors.initials: M
authors.lastname: Roose-Girma
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D020964:Embryo Loss; D047108:Embryonic Development; D004751:Enteritis / Q000473:pathology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D055879:Gene Knock-In Techniques; D007420:Intestine, Large / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D009336:Necrosis; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D014409:Tumor Necrosis Factor-alpha; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8