title: Editing of Cellular Self-RNAs by Adenosine Deaminase ADAR1 Suppresses Innate Immune Stress Responses.
abstract: Adenosine deaminases acting on double-stranded RNA (ADARs) catalyze the deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA structures, a process known as A-to-I RNA editing. dsRNA is an important trigger of innate immune responses, including interferon (IFN) production and action. We examined the role of A-to-I RNA editing by two ADARs, ADAR1 and ADAR2, in the sensing of self-RNA in the absence of pathogen infection, leading to activation of IFN-induced, RNA-mediated responses in mouse embryo fibroblasts. IFN treatment of Adar1(-/-) cells lacking both the p110 constitutive and p150 IFN-inducible ADAR1 proteins induced formation of stress granules, whereas neither wild-type (WT) nor Adar2(-/-) cells displayed a comparable stress granule response following IFN treatment. Phosphorylation of protein synthesis initiation factor eIF2α at serine 51 was increased in IFN-treated Adar1(-/-) cells but not in either WT or Adar2(-/-) cells following IFN treatment. Analysis by deep sequencing of mouse exonic loci containing A-to-I-editing sites revealed that the majority of editing in mouse embryo fibroblasts was carried out by ADAR1. IFN treatment increased editing in both WT and Adar2(-/-) cells but not in either Adar1(-/-) or Adar1(-/-) (p150) cells or Stat1(-/-) or Stat2(-/-) cells. Hyper-edited sites found in predicted duplex structures showed strand bias of editing for some RNAs. These results implicate ADAR1 p150 as the major A-to-I editor in mouse embryo fibroblasts, acting as a feedback suppressor of innate immune responses otherwise triggered by self-RNAs possessing regions of double-stranded character.
authors.affiliation: From the Department of Molecular, Cellular and Developmental Biology and.
authors.forename: Cyril X
authors.initials: CX
authors.lastname: George
authors.affiliation: the Department of Genetics, Stanford University, Stanford, California 94305.
authors.forename: Gokul
authors.initials: G
authors.lastname: Ramaswami
authors.affiliation: the Department of Genetics, Stanford University, Stanford, California 94305.
authors.forename: Jin Billy
authors.identifier: http://orcid.org/0000-0003-0713-1399
authors.initials: JB
authors.lastname: Li
authors.affiliation: From the Department of Molecular, Cellular and Developmental Biology and the Biomolecular Sciences and Engineering Program, University of California, Santa Barbara, California 93106 and samuel@lifesci.ucsb.edu.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Samuel
mesh_terms: D000243:Adenosine Deaminase / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism; D003641:Deamination; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007108:Immune Tolerance; D007113:Immunity, Innate; D016898:Interferon-alpha / Q000502:physiology; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017393:RNA Editing; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000502:physiology; D015398:Signal Transduction
chemical_list: D015852:Eukaryotic Initiation Factor-2; D016898:Interferon-alpha; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; C000599465:ADAR1 protein, mouse; C000595151:ADAR2 protein, mouse; D000243:Adenosine Deaminase
keywords: RNA editing; adenosine deaminase acting on RNA (ADAR); innate immunity; interferon; protein kinase RNA-activated (PKR); stress granule
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