RT Journal Article SR Electronic T1 ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.12.04.411702 DO 10.1101/2020.12.04.411702 A1 Richard de Reuver A1 Evelien Dierick A1 Bartosz Wiernicki A1 Katrien Staes A1 Leen Seys A1 Ellen De Meester A1 Tuur Muyldermans A1 Alexander Botzki A1 Bart Lambrecht A1 Filip Van Nieuwerburgh A1 Peter Vandenabeele A1 Jonathan Maelfait YR 2020 UL http://biorxiv.org/content/early/2020/12/04/2020.12.04.411702.abstract AB Loss-of-function of ADAR1 causes the severe autoinflammatory disease Aicardi-Goutières Syndrome (AGS). ADAR1 converts adenosines into inosines within double-stranded (ds) RNA. This process called A-to-I editing masks self-dsRNA from detection by the antiviral dsRNA sensor MDA5. ADAR1 binds to dsRNA in both the canonical A-form and in the poorly defined Z-conformation (Z-RNA). Mutations in the Z-RNA binding Zα-domain of ADAR1 are common in AGS patients. How loss of ADAR1/Z-RNA interaction contributes to disease development is unknown. Using ADAR1 Zα-domain mutant human cells and knock-in mice, we demonstrate that abrogated binding of ADAR1 to Z-RNA leads to reduced A-to-I editing of dsRNA structures formed by pairing of inversely oriented SINEs. As a result, ADAR1 Zα-domain mutant human cells and transgenic mice develop a spontaneous MDA5-dependent immune response. This shows that the interaction between ADAR1 and Z-RNA restricts sensing of self-dsRNA and prevents AGS development.Competing Interest StatementThe authors have declared no competing interest.