The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA

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. [Display omitted] •Adar1 mutant mouse embryonic lethality is rescued in Adar1; Mavs double mutants•Aberrant antiviral responses in the Adar1 mutant are due to loss of RNA editing•Human ADAR1 mutations causing AGS affect primarily the interferon-inducible isoform•We propose that inosine helps innate immunity to distinguish cellular from viral RNA Mice lacking Adar1 have a heightened immune response and stress-related apoptosis. Mannion et al. demonstrate that this mutation can be rescued to birth by generating a double mutant with Mavs, an innate immune gene, indicating the central role ADAR1 plays in innate immunity.