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
Affiliations
Richard de Reuver
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Evelien Dierick
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Bartosz Wiernicki
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Katrien Staes
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Leen Seys
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
Ellen De Meester
Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium
Tuur Muyldermans
VIB Bioinformatics Core, VIB, 9052 Ghent, Belgium
Alexander Botzki
VIB Bioinformatics Core, VIB, 9052 Ghent, Belgium
Bart N. Lambrecht
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, 3015 GJ Rotterdam, the Netherlands
Filip Van Nieuwerburgh
NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
Peter Vandenabeele
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
Jonathan Maelfait
VIB-UGent Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium; Corresponding author
Summary: 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.
