title: Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo.
abstract: The serine/threonine kinase RIPK1 is recruited to TNFR1 to mediate proinflammatory signaling and to regulate TNF-induced cell death. A RIPK1 deficiency results in perinatal lethality, impaired NFκB and MAPK signaling, and sensitivity to TNF-induced apoptosis. Chemical inhibitor and in vitro-reconstitution studies suggested that RIPK1 displays distinct kinase activity-dependent and -independent functions. To determine the contribution of RIPK1 kinase to inflammation in vivo, we generated knock-in mice endogenously expressing catalytically inactive RIPK1 D138N. Unlike Ripk1(-/-) mice, which die shortly after birth, Ripk1(D138N/D138N) mice are viable. Cells expressing RIPK1 D138N are resistant to TNF- and polyinosinic-polycytidylic acid-induced necroptosis in vitro, and Ripk1(D138N/D138N) mice are protected from TNF-induced shock in vivo. Moreover, Ripk1(D138N/D138N) mice fail to control vaccinia virus replication in vivo. This study provides genetic evidence that the kinase activity of RIPK1 is not required for survival but is essential for TNF-, TRIF-, and viral-initiated necroptosis.
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Polykratis
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hermance
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Zelic
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Roderick
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Chun
authors.initials: C
authors.lastname: Kim
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Trieu-My
authors.initials: TM
authors.lastname: Van
authors.affiliation: Genentech, San Francisco, CA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Francis K M
authors.initials: FKM
authors.lastname: Chan
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
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
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D055879:Gene Knock-In Techniques; D007035:Hypothermia / Q000139:chemically induced / Q000401:mortality*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D009336:Necrosis / Q000139:chemically induced / Q000276:immunology*; D011070:Poly I-C / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000254:growth & development / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016328:NF-kappa B; D011070:Poly I-C; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse; C506236:Tnfrsf1a protein, mouse; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse