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 Adar^E374A 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.

ADAR RNA 编辑酶是高亲和力 dsRNA 结合蛋白，可将前 mRNA 发夹中的腺苷脱氨基为肌苷，并发挥不依赖于编辑的作用。我们利用 CRISPR/Cas9 生成了编码催化失活 Adar 的果蝇 Adar ^E374A突变株。我们证明，Adar 腺苷脱氨活性对于正常运动是必需的，并且可以预防年龄依赖性神经变性。当催化失活蛋白以高于生理水平的表达时，可以挽救Adar突变体的神经变性，这也表明了编辑无关的效应。此外，Adar RNA编辑活性的丧失会导致先天免疫诱导，这表明果蝇Adar尽管是哺乳动物ADAR2的同源物，但也具有与哺乳动物ADAR1相似的功能。果蝇Adar突变体中的先天免疫诱导受到 Dicer-2 沉默的抑制，Dicer-2 具有类似于 MDA5 的 RNA 解旋酶结构域，可感知哺乳动物Adar1突变体中未经编辑的 dsRNA。我们的工作表明，果蝇中的单一 Adar 酶出人意料地具有双重功能。