Disruption of Z-RNA–binding of ADAR1 induces Aicardi-Goutières syndrome–like encephalopathy in mice

SUMMARY ADAR1 p150 is an enzyme responsible for adenosine-to-inosine RNA editing. Deletion of ADAR1 p150 results in embryonic lethality with a type I interferon (IFN) signature, caused by aberrant MDA5 sensing unedited transcripts. ADAR1 p150 contains a unique Z-DNA/RNA–binding domain α (Zα); however, the role of this domain remains unknown. A mutation has been identified in this domain in patients with Aicardi-Goutières syndrome (AGS), an inherited interferonopathy, suggesting an essential role in avoiding MDA5 activation. Here, we show that a mutation in the Zα domain reduces the editing activity of ADAR1 p150 by comparing activity between wild-type and mutated isoforms expressed in Adar1/Adar2 knockout cells. Furthermore, we created Zα domain–mutated knock-in mice, which displayed severe growth retardation with abnormal organ development, including AGS-like encephalopathy with a type I IFN signature. These abnormalities were ameliorated by the concurrent deletion of MDA5. Collectively, Z-RNA–recognition contributes to ADAR1 p150–mediated RNA editing, which prevents MDA5 activation.