Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila
Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila
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DOI：
10.1038/s41467-020-15435-1
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发表时间：
2020-03-27
影响因子：
16.6
通讯作者：
Keegan, Liam P.
中科院分区：
文献类型：
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作者：
Deng, Patricia;Khan, Anzer;Keegan, Liam P.
阿达尔RNA编辑酶是高亲和力的dsRNA结合蛋白，其将前mRNA发夹中的腺苷脱氨基为肌苷，并且还发挥编辑非依赖性效应。我们产生了果蝇阿达尔（E374 A）突变株，其编码具有CRISPR/Cas9的催化失活的阿达尔。我们证明，阿达尔腺苷脱氨活性是必要的正常运动，并防止年龄依赖性神经退行性变。当以高于生理水平的水平表达时，催化失活的蛋白质可以挽救阿达尔突变体中的神经变性，这也表明了非编辑依赖性效应。此外，阿达尔RNA编辑活性的丧失导致先天免疫诱导，表明果蝇阿达尔尽管是哺乳动物ADAR 2的同源物，但也具有与哺乳动物ADAR 1相似的功能。果蝇阿达尔突变体中的先天免疫诱导受到Dicer-2沉默的抑制，Dicer-2具有与MDA 5相似的RNA解旋酶结构域，其感测哺乳动物Adar 1突变体中未编辑的dsRNA。我们的工作表明，果蝇中的单个阿达尔酶出乎意料地具有双重功能。人类RNA编辑酶ADAR 1和ADAR 2分别是先天免疫功能和神经功能所必需的。在这里，作者表明，果蝇阿达尔具有先天免疫和大脑功能，尽管是哺乳动物ADAR 2的同源物。
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. Human RNA editing enzymes ADAR1 and ADAR2 are required for innate immune functions and neurological functions, respectively. Here, the authors show that Drosophila Adar has both innate immune and brain functions, despite being the homolog of mammalian ADAR2.