The RNA-editing enzyme ADAR1 controls innate immune responses to RNA

Cell Rep. 2014 Nov 20;9(4):1482-94. doi: 10.1016/j.celrep.2014.10.041. Epub 2014 Nov 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism*
  • Animals
  • Autoimmune Diseases of the Nervous System / genetics
  • Autoimmune Diseases of the Nervous System / immunology
  • Crosses, Genetic
  • Cytokines / metabolism
  • Embryo Loss / pathology
  • Embryo, Mammalian / pathology
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Immunity, Innate*
  • Inflammation Mediators / metabolism
  • Inosine / metabolism
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Nervous System Malformations / genetics
  • Nervous System Malformations / immunology
  • Phenotype
  • RNA Editing*
  • RNA, Double-Stranded / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Receptors, Interferon / metabolism
  • Survival Analysis
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism
  • Uracil / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • IPS-1 protein, mouse
  • Inflammation Mediators
  • RNA, Double-Stranded
  • RNA-Binding Proteins
  • Receptors, Interferon
  • Tumor Suppressor Protein p53
  • Uracil
  • Inosine
  • ADAR protein, human
  • ADAR1 protein, mouse
  • Adenosine Deaminase

Supplementary concepts

  • Aicardi-Goutieres syndrome

Associated data

  • GEO/GSE62917