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Publication : ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation.

First Author  de Reuver R Year  2022
Journal  Nature Volume  607
Issue  7920 Pages  784-789
PubMed ID  35859175 Mgi Jnum  J:330287
Mgi Id  MGI:7367314 Doi  10.1038/s41586-022-04974-w
Citation  de Reuver R, et al. (2022) ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature 607(7920):784-789
abstractText  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-Goutieres syndrome (AGS)(2). In mice, complete loss of ADAR1 activity is embryonically lethal(3-6), and mutations similar to those found in patients with AGS cause autoinflammation(7-12). Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR(3,7-10,13,14). 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 Zalpha domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Zalpha 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.
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