title: RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition.
abstract: The pronecrotic kinase, receptor interacting protein (RIP1, also called RIPK1) mediates programmed necrosis and, together with its partner, RIP3 (RIPK3), drives midgestational death of caspase 8 (Casp8)-deficient embryos. RIP1 controls a second vital step in mammalian development immediately after birth, the mechanism of which remains unresolved. Rip1(-/-) mice display perinatal lethality, accompanied by gross immune system abnormalities. Here we show that RIP1 K45A (kinase dead) knockin mice develop normally into adulthood, indicating that development does not require RIP1 kinase activity. In the face of complete RIP1 deficiency, cells develop sensitivity to RIP3-mixed lineage kinase domain-like-mediated necroptosis as well as to Casp8-mediated apoptosis activated by diverse innate immune stimuli (e.g., TNF, IFN, double-stranded RNA). When either RIP3 or Casp8 is disrupted in combination with RIP1, the resulting double knockout mice exhibit slightly prolonged survival over RIP1-deficient animals. Surprisingly, triple knockout mice with combined RIP1, RIP3, and Casp8 deficiency develop into viable and fertile adults, with the capacity to produce normal levels of myeloid and lymphoid lineage cells. Despite the combined deficiency, these mice sustain a functional immune system that responds robustly to viral challenge. A single allele of Rip3 is tolerated in Rip1(-/-)Casp8(-/-)Rip3(+/-) mice, contrasting the need to eliminate both alleles of either Rip1 or Rip3 to rescue midgestational death of Casp8-deficient mice. These observations reveal a vital kinase-independent role for RIP1 in preventing pronecrotic as well as proapoptotic signaling events associated with life-threatening innate immune activation at the time of mammalian parturition.
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; wkaiser@emory.edu peter.j.gough@gsk.com mocarski@emory.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Kaiser
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Daley-Bauer
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Roshan J
authors.initials: RJ
authors.lastname: Thapa
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Pratyusha
authors.initials: P
authors.lastname: Mandal
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Berger
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Chunzi
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Aarthi
authors.initials: A
authors.lastname: Sundararajan
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Linda
authors.initials: L
authors.lastname: Roback
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Speck
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426 wkaiser@emory.edu peter.j.gough@gsk.com mocarski@emory.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111; and.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; wkaiser@emory.edu peter.j.gough@gsk.com mocarski@emory.edu.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mocarski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D053181:Caspase 8 / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055879:Gene Knock-In Techniques; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000276:immunology*; D036801:Parturition / Q000276:immunology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D017931:DNA Primers; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8
keywords: MLKL; herpesvirus; interferon