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, Liam P. Keegan

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25 Scopus citations


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.

Original languageEnglish
Article number1580
JournalNature Communications
Issue number1
StatePublished - 27 Mar 2020

Bibliographical note

Funding Information:
The authors thank Jianquan Ni and the Tsinghua Fly Center for providing fly CRISPR reagents. We thank members of the RNA and Immunity and Li lab, Andrew Fire, Joseph Lipsick, Hunter Fraser, and Huaying Fang for helpful discussions and Anne Sapiro for assistance in figure preparation. This work was supported by the National Institutes of Health, (Grant Numbers R01GM102484, R01GM124215, and R01MH115080), and by the Ellison Medical Foundation, grant number AG-NS-0959-12 (to J.B.L.). P.D. was supported by the Stanford Center for Computational, Evolutionary and Human Genomics (CEHG), National Science Foundation Graduate Research Fellowship (no. DGE-114747), Stanford Genome Training Program (NIH T32 HG000044), and Cell and Molecular Biology Training Program (NIH T32 GM007276). This work was supported by an MRC Capacity Building Area Research Studentship to L. McG; by MND Scotland Prize Studentship award (to LK for XL), and by the Medical Research Council UK (U.1275.01.005.00001.01) to MAO. This work was also supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No 621368 (to MO’C). The work was supported from European Regional Development Fund-Project “National infrastructure for biological and medical imaging” (No. CZ.02.1.01/0.0/0.0/16_013/0001775) and by Czech Science Foundation, project No. 19-16963S to LK.

Publisher Copyright:
© 2020, The Author(s).


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