@article {Nakahama2020.12.16.422984, author = {Taisuke Nakahama and Yuki Kato and Toshiharu Shibuya and Jung In Kim and Tuangtong Vongpipatana and Hiroyuki Todo and Yanfang Xing and Yukio Kawahara}, title = {Disruption of Z-RNA{\textendash}binding of ADAR1 induces Aicardi-Gouti{\`e}res syndrome{\textendash}like encephalopathy in mice}, elocation-id = {2020.12.16.422984}, year = {2020}, doi = {10.1101/2020.12.16.422984}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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{\textendash}binding domain α (Zα); however, the role of this domain remains unknown. A mutation has been identified in this domain in patients with Aicardi-Gouti{\`e}res 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{\textendash}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{\textendash}recognition contributes to ADAR1 p150{\textendash}mediated RNA editing, which prevents MDA5 activation.Competing Interest StatementThe authors have declared no competing interest.}, URL = {https://www.biorxiv.org/content/early/2020/12/16/2020.12.16.422984}, eprint = {https://www.biorxiv.org/content/early/2020/12/16/2020.12.16.422984.full.pdf}, journal = {bioRxiv} }