ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation

Richard Reuver, Simon Verdonck, Evelien Dierick, Josephine Nemegeer, Eline Hessmann, Sadeem Ahmad, Maude Jans, Gillian Blancke, Filip Nieuwerburgh, Alexander Botzki, Lars Vereecke, Geert Loo, Wim Declercq, Sun Hur, Peter Vandenabeele and Jonathan Maelfait ()
Additional contact information
Richard Reuver: VIB-UGent Center for Inflammation Research
Simon Verdonck: VIB-UGent Center for Inflammation Research
Evelien Dierick: VIB-UGent Center for Inflammation Research
Josephine Nemegeer: VIB-UGent Center for Inflammation Research
Eline Hessmann: VIB-UGent Center for Inflammation Research
Sadeem Ahmad: Harvard Medical School, Howard Hughes Medical Institute
Maude Jans: VIB-UGent Center for Inflammation Research
Gillian Blancke: VIB-UGent Center for Inflammation Research
Filip Nieuwerburgh: Ghent University
Alexander Botzki: VIB
Lars Vereecke: VIB-UGent Center for Inflammation Research
Geert Loo: VIB-UGent Center for Inflammation Research
Wim Declercq: VIB-UGent Center for Inflammation Research
Sun Hur: Harvard Medical School, Howard Hughes Medical Institute
Peter Vandenabeele: VIB-UGent Center for Inflammation Research
Jonathan Maelfait: VIB-UGent Center for Inflammation Research

Nature, 2022, vol. 607, issue 7920, 784-789

Abstract: Abstract The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)1. In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi–Goutières syndrome (AGS)2. In mice, complete loss of ADAR1 activity is embryonically lethal3–6, and mutations similar to those found in patients with AGS cause autoinflammation7–12. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR3,7–10,13,14. Here we show that ADAR1 also inhibits the spontaneous activation of the left-handed Z-nucleic acid sensor ZBP1. Activation of ZBP1 elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis of ADAR1-deficient cells. ZBP1 contributes to the embryonic lethality of Adar-knockout mice, and it drives early mortality and intestinal cell death in mice deficient in the expression of both ADAR and MAVS. The Z-nucleic-acid-binding Zα domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Zα domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through the pairing of inverted Alu repeats, which can otherwise induce ZBP1 activation. This shows that recognition of Alu duplex RNA by ZBP1 may contribute to the pathological features of AGS that result from the loss of ADAR1 function.

Date: 2022
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DOI: 10.1038/s41586-022-04974-w

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