Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila

Patricia Deng, Anzer Khan, Dionna Jacobson, Nagraj Sambrani, Leeanne McGurk, Xianghua Li, Aswathy Jayasree, Jan Hejatko, Galit Shohat-Ophir, Mary A. O’Connell, Jin Billy Li () and Liam P. Keegan ()
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Patricia Deng: Stanford University
Anzer Khan: Central European Institute of Technology, Masaryk University
Dionna Jacobson: Stanford University
Nagraj Sambrani: Central European Institute of Technology, Masaryk University
Leeanne McGurk: MRC Institute of Genetics and Molecular Medicine, Western General Hospital
Xianghua Li: MRC Institute of Genetics and Molecular Medicine, Western General Hospital
Aswathy Jayasree: Central European Institute of Technology, Masaryk University
Jan Hejatko: Central European Institute of Technology, Masaryk University
Galit Shohat-Ophir: The Faculty of Life Sciences and The Multidisciplinary Brain Research Center, Bar Ilan University
Mary A. O’Connell: Central European Institute of Technology, Masaryk University
Jin Billy Li: Stanford University
Liam P. Keegan: Central European Institute of Technology, Masaryk University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract ADAR RNA editing enzymes are high-affinity dsRNA-binding proteins that deaminate adenosines to inosines in pre-mRNA hairpins and also exert editing-independent effects. We generated a Drosophila AdarE374A mutant strain encoding a catalytically inactive Adar with CRISPR/Cas9. We demonstrate that Adar adenosine deamination activity is necessary for normal locomotion and prevents age-dependent neurodegeneration. The catalytically inactive protein, when expressed at a higher than physiological level, can rescue neurodegeneration in Adar mutants, suggesting also editing-independent effects. Furthermore, loss of Adar RNA editing activity leads to innate immune induction, indicating that Drosophila Adar, despite being the homolog of mammalian ADAR2, also has functions similar to mammalian ADAR1. The innate immune induction in fly Adar mutants is suppressed by silencing of Dicer-2, which has a RNA helicase domain similar to MDA5 that senses unedited dsRNAs in mammalian Adar1 mutants. Our work demonstrates that the single Adar enzyme in Drosophila unexpectedly has dual functions.

Date: 2020
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DOI: 10.1038/s41467-020-15435-1

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