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

Nat Commun. 2020 Mar 27;11(1):1580. doi: 10.1038/s41467-020-15435-1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Deaminase / chemistry
  • Adenosine Deaminase / genetics*
  • Adenosine Monophosphate / metabolism
  • Aging / pathology
  • Animals
  • Brain / metabolism*
  • Catalysis
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / immunology*
  • Gene Expression Regulation
  • Immunity, Innate / genetics*
  • Locomotion
  • Nerve Degeneration / pathology
  • Point Mutation / genetics
  • Protein Domains
  • RNA Editing / genetics*
  • RNA Helicases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Ribonuclease III / metabolism

Substances

  • Drosophila Proteins
  • RNA, Messenger
  • Adenosine Monophosphate
  • DCR-2 protein, Drosophila
  • Ribonuclease III
  • Adar protein, Drosophila
  • Adenosine Deaminase
  • RNA Helicases