ADAR1 suppresses the recognition of self dsRNA

The conversion of adenosine to inosine is catalysed on double-stranded RNA (dsRNA) by ADAR deaminases. ADAR1-null mice die in utero owing to failed erythropoiesis and liver disintegration, but whether this is caused by defects in RNA editing was unknown. Liddicoat et al. confirmed that this is the case by recapitulating a similar phenotype in mice with editing-deficient ADAR1 (Adar1^E861A/E861A). The absence of RNA editing led to upregulation of interferon-stimulated genes, similar to those activated in vitro by dsRNAs containing adenosine, but not inosine, demonstrating that editing by ADAR1 suppresses the interferon response in homeostatic conditions. Many editing sites were found in the 3′ UTRs of three erythropoiesis genes; these were predicted to form long dsRNA stretches in unedited but not in edited transcripts. Knocking out MDA5 — which is a sensor of viral dsRNA and activator of the interferon response — in Adar1^E861A/E861A mice rescued their phenotype. Thus, sensing of unedited endogenous dsRNAs by MDA5 activates erythropoiesis-detrimental interferon responses.