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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 Lambrecht, Filip Van Nieuwerburgh, Peter Vandenabeele, View ORCID ProfileJonathan Maelfait
doi: https://doi.org/10.1101/2020.12.04.411702
Richard de Reuver
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. VIB-UGent Center for Inflammation Research, Ghent 9052, Belgium
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Evelien Dierick
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. VIB-UGent Center for Inflammation Research, Ghent 9052, Belgium
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Bartosz Wiernicki
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. VIB-UGent Center for Inflammation Research, Ghent 9052, Belgium
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Katrien Staes
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. VIB-UGent Center for Inflammation Research, Ghent 9052, Belgium
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Leen Seys
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
3Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium
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Ellen De Meester
4NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, Ghent, Belgium
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Tuur Muyldermans
5VIB Bioinformatics Core, VIB, 9052 Ghent, Belgium
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Alexander Botzki
5VIB Bioinformatics Core, VIB, 9052 Ghent, Belgium
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Bart Lambrecht
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
3Department of Internal Medicine and Pediatrics, Ghent University, Ghent 9000, Belgium
6Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, Rotterdam 3015 GJ, the Netherlands
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Filip Van Nieuwerburgh
4NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, Ghent, Belgium
7Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, Ghent, Belgium
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Peter Vandenabeele
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. VIB-UGent Center for Inflammation Research, Ghent 9052, Belgium
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Jonathan Maelfait
1VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium
2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium. VIB-UGent Center for Inflammation Research, Ghent 9052, Belgium
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  • ORCID record for Jonathan Maelfait
  • For correspondence: jonathan.maelfait@irc.vib-ugent.be
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Summary

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 Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 04, 2020.
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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 Lambrecht, Filip Van Nieuwerburgh, Peter Vandenabeele, Jonathan Maelfait
bioRxiv 2020.12.04.411702; doi: https://doi.org/10.1101/2020.12.04.411702
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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 Lambrecht, Filip Van Nieuwerburgh, Peter Vandenabeele, Jonathan Maelfait
bioRxiv 2020.12.04.411702; doi: https://doi.org/10.1101/2020.12.04.411702

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