Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1016/j.celrep.2014.10.041

Type

Journal article

Journal

Cell Rep

Publication Date

20/11/2014

Volume

9

Pages

1482 - 1494

Keywords

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