Mutations in the gene encoding the RNA-editing enzyme ADAR1 lead to Aicardi-Goutières syndrome, an autoinflammatory disease. Similarly, ADAR1 deficiency in mice results in embryonic death characterized by exuberant expression of type I interferon. In Immunity, Pestal et al. show that ADAR1 suppresses activation of the intracellular RNA sensor pathway mediated by Mda5 and MAVS. Adar-null embryos are 'rescued' by loss of expression of either Mda5 or MAVS. RNA sequencing analyses reveal that only 20% of the genes dysregulated in Adar−/− embryos are MAVS-dependent interferon-stimulated genes, whereas additional defects in organ development, intestinal homeostasis and hematopoiesis are apparent in Adar−/−Mavs−/− neonates. Adar encodes two isoforms, p150 and p110, which have non-redundant functions, as mice lacking p150 are 'rescued' by MAVS deficiency but still show loss of B cell development and intestinal abnormalities. The p150 isoform might edit long duplex RNAs that serve as Mda5 ligands, in addition to editing other RNA targets.

Immunity 43, 933–944 (2015)