ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation

Richard de Reuver, Evelien Dierick, Bartosz Wiernicki, Katrien Staes, Leen Seys, Ellen De Meester, Tuur Muyldermans, Alexander Botzki, Bart N. Lambrecht, Filip Van Nieuwerburgh, Peter Vandenabeele, Jonathan Maelfait*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

59 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article number109500
JournalCell Reports
Volume36
Issue number6
DOIs
Publication statusPublished - 10 Aug 2021

Bibliographical note

Funding 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.

Publisher Copyright: © 2021 The Authors

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