title: The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.
abstract: The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform.
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: Mannion
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Greenwood
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Young
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cox
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: James
authors.initials: J
authors.lastname: Brindle
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Read
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Nellåker
authors.affiliation: Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/5, 1030 Vienna, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Vesely
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.affiliation: Institute of Structural and Molecular Biology, Michael Swann Building, School of Biological Sciences, Kings Buildings, West Mains Road, Edinburgh EH9 3JG, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaughlin
authors.affiliation: Department of Chromosome Biology, Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/5, 1030 Vienna, Austria.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jantsch
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Dorin
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Adams
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: A D J
authors.initials: AD
authors.lastname: Scadden
authors.affiliation: Department of Molecular Biosciences, Wenner Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Ohman
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK. Electronic address: liam.keegan@igmm.ed.ac.uk.
authors.forename: Liam P
authors.initials: LP
authors.lastname: Keegan
authors.affiliation: MRC Human Genetics Unit, IGMM, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK; Department of Molecular Biosciences, Wenner Gren Institute, Stockholm University, 106 91 Stockholm, Sweden. Electronic address: mary.oconnell@igmm.ed.ac.uk.
authors.forename: Mary A
authors.initials: MA
authors.lastname: O'Connell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D020964:Embryo Loss / Q000473:pathology; D004622:Embryo, Mammalian / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007288:Inosine / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D017393:RNA Editing; D012330:RNA, Double-Stranded / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000378:metabolism; D016019:Survival Analysis; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014498:Uracil / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000243:Adenosine Deaminase; D016207:Cytokines; D018836:Inflammation Mediators; D007288:Inosine; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D017471:Receptors, Interferon; D016159:Tumor Suppressor Protein p53; D014498:Uracil; C512612:MAVS protein, mouse; C000595356:ADAR protein, human; C000599465:ADAR1 protein, mouse