title: RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3.
abstract: Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and -independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1(-/-) mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1(-/-)tnfr1(-/-) mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Weinlich
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Rodriguez
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Cripps
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarato
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Verbist
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Taylor L
authors.initials: TL
authors.lastname: Brewer
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Llambi
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Gong
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005804:Genes, Lethal; D007249:Inflammation / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053181:Caspase 8; D053200:Fas-Associated Death Domain Protein; D007372:Interferons; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D048069:Tumor Necrosis Factors; C505534:Fadd protein, mouse; C476286:Ticam1 protein, mouse; C506236:Tnfrsf1a protein, mouse; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse