Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Bioinformatics and Biostatistics STP, The Francis Crick Institute, London, NW1 1AT, UK.
Immunity. 2021 Sep 14;54(9):1961-1975.e5. doi: 10.1016/j.immuni.2021.08.011.
Nucleic acids are powerful triggers of innate immunity and can adopt the Z-conformation, an unusual left-handed double helix. Here, we studied the biological function(s) of Z-RNA recognition by the adenosine deaminase ADAR1, mutations in which cause Aicardi-Goutières syndrome. Adar1 mice, bearing two point mutations in the Z-nucleic acid binding (Zα) domain that abolish Z-RNA binding, displayed spontaneous induction of type I interferons (IFNs) in multiple organs, including in the lung, where both stromal and hematopoietic cells showed IFN-stimulated gene (ISG) induction. Lung neutrophils expressed ISGs induced by the transcription factor IRF3, indicating an initiating role for neutrophils in this IFN response. The IFN response in Adar1 mice required the adaptor MAVS, implicating cytosolic RNA sensing. Adenosine-to-inosine changes were enriched in transposable elements and revealed a specific requirement of ADAR1's Zα domain in editing of a subset of RNAs. Thus, endogenous RNAs in Z-conformation have immunostimulatory potential curtailed by ADAR1, with relevance to autoinflammatory disease in humans.
核酸是先天免疫的强大触发物，并且可以采用 Z 构象，这是一种异常的左手双螺旋。在这里，我们研究了腺苷脱氨酶 ADAR1 识别 Z-RNA 的生物学功能（多个），该基因突变会导致 Aicardi-Goutières 综合征。携带两个点突变的 Adar1 小鼠在多个器官中自发诱导 I 型干扰素（IFN），包括在肺中，基质细胞和造血细胞均显示 IFN 刺激基因（ISG）诱导。肺中性粒细胞表达由转录因子 IRF3 诱导的 ISGs，表明中性粒细胞在这种 IFN 反应中起启动作用。Adar1 小鼠中的 IFN 反应需要衔接蛋白 MAVS，这暗示了细胞质 RNA 感应的作用。腺苷到肌苷的变化在转座元件中富集，并揭示了 ADAR1 的 Zα 结构域在一组 RNA 编辑中的特定要求。因此，Z 构象中的内源性 RNA 具有免疫刺激性潜能，但被 ADAR1 所限制，这与人类的自身炎症性疾病有关。
