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ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation

(2022) NATURE. 607(7920). p.784-789
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Abstract
The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)(.) In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutieres syndrome (AGS). In mice, complete loss of ADAR1 activity is embryonically lethal, and mutations similar to those found in patients with AGS cause autoinflammation. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR. 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 Z alpha domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Z alpha 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.
Keywords
DOUBLE-STRANDED-RNA, Z-ALPHA DOMAIN, ADENOSINE-DEAMINASE, ENDOGENOUS RNA, MUTATIONS, BINDING, INDUCE, CELL, NECROPTOSIS, DEFICIENCY

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MLA
de Reuver, Richard, et al. “ADAR1 Prevents Autoinflammation by Suppressing Spontaneous ZBP1 Activation.” NATURE, vol. 607, no. 7920, 2022, pp. 784–89, doi:10.1038/s41586-022-04974-w.
APA
de Reuver, R., Verdonck, S., Dierick, E., Nemegeer, J., Hessmann, E., Ahmad, S., … Maelfait, J. (2022). ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. NATURE, 607(7920), 784–789. https://doi.org/10.1038/s41586-022-04974-w
Chicago author-date
Reuver, Richard de, Simon Verdonck, Evelien Dierick, Josephine Nemegeer, Eline Hessmann, Sadeem Ahmad, Maude Jans, et al. 2022. “ADAR1 Prevents Autoinflammation by Suppressing Spontaneous ZBP1 Activation.” NATURE 607 (7920): 784–89. https://doi.org/10.1038/s41586-022-04974-w.
Chicago author-date (all authors)
de Reuver, Richard, Simon Verdonck, Evelien Dierick, Josephine Nemegeer, Eline Hessmann, Sadeem Ahmad, Maude Jans, Gillian Blancke, Filip Van Nieuwerburgh, Alexander Botzki, Lars Vereecke, Geert van Loo, Wim Declercq, Sun Hur, Peter Vandenabeele, and Jonathan Maelfait. 2022. “ADAR1 Prevents Autoinflammation by Suppressing Spontaneous ZBP1 Activation.” NATURE 607 (7920): 784–789. doi:10.1038/s41586-022-04974-w.
Vancouver
1.
de Reuver R, Verdonck S, Dierick E, Nemegeer J, Hessmann E, Ahmad S, et al. ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. NATURE. 2022;607(7920):784–9.
IEEE
[1]
R. de Reuver et al., “ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation,” NATURE, vol. 607, no. 7920, pp. 784–789, 2022.
@article{8763512,
  abstract     = {{The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)(.) In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutieres syndrome (AGS). In mice, complete loss of ADAR1 activity is embryonically lethal, and mutations similar to those found in patients with AGS cause autoinflammation. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR. 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 Z alpha domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Z alpha 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.}},
  articleno    = {{s41586-022-04974-w}},
  author       = {{de Reuver, Richard and Verdonck, Simon and Dierick, Evelien and Nemegeer, Josephine and Hessmann, Eline and Ahmad, Sadeem and Jans, Maude and Blancke, Gillian and Van Nieuwerburgh, Filip and Botzki, Alexander and Vereecke, Lars and van Loo, Geert and Declercq, Wim and Hur, Sun and Vandenabeele, Peter and Maelfait, Jonathan}},
  issn         = {{0028-0836}},
  journal      = {{NATURE}},
  keywords     = {{DOUBLE-STRANDED-RNA,Z-ALPHA DOMAIN,ADENOSINE-DEAMINASE,ENDOGENOUS RNA,MUTATIONS,BINDING,INDUCE,CELL,NECROPTOSIS,DEFICIENCY}},
  language     = {{eng}},
  number       = {{7920}},
  pages        = {{s41586-022-04974-w:784--s41586-022-04974-w:789}},
  title        = {{ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation}},
  url          = {{http://dx.doi.org/10.1038/s41586-022-04974-w}},
  volume       = {{607}},
  year         = {{2022}},
}

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