Loss of function of adenosine deaminase acting on double-stranded RNA (dsRNA)-1 (ADAR1) causes the severe autoinflammatory disease Aicardi-Goutières syndrome (AGS). ADAR1 converts adenosines into inosines within dsRNA. 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 the poorly defined Z conformation (Z-RNA). Mutations in the Z-RNA-binding Zα domain of ADAR1 are common in patients with AGS. How loss of ADAR1/Z-RNA interaction contributes to disease development is unknown. We demonstrate that abrogated binding of ADAR1 to Z-RNA leads to reduced A-to-I editing of dsRNA structures formed by base pairing of inversely oriented short interspersed nuclear elements. Preventing ADAR1 binding to Z-RNA triggers an MDA5/MAVS-mediated type I interferon response and leads to the development of lethal autoinflammation in mice. This shows that the interaction between ADAR1 and Z-RNA restricts sensing of self-dsRNA and prevents AGS development.
|Publication status||Published - 10 Aug 2021|
Bibliographical noteFunding Information:
This research would not have been possible without support from the following funding agencies. R.d.R. was supported by a Ghent University BOF PhD fellowship (01D24020). L.S. was supported by an FWO postdoctoral fellowship (1236420N). Research in the Vandenabeele group is supported by EOS MODEL-IDI (FWO grant 30826052), FWO research grants (G.0E04.16N, G.0C76.18N, G.0B71.18N, and G.0B96.20N), Methusalem (BOF16/MET_V/007), the Foundation Against Cancer (F/2016/865 and F/2020/1505), CRIG and GIGG consortia, and VIB. J.M. was supported by an Odysseus II Grant (G0H8618N) from the Research Foundation Flanders and by Ghent University.
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