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^mZα/mZα 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^mZα/mZα 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因素，可以采用 Z 构象，一种不寻常的左手双螺旋结构。在这里，我们研究了腺苷脱氨酶 ADAR1 识别 Z-RNA 的生物学功能，这些突变会导致 Aicardi-Goutières 综合征。Adar1 ^mZα/mZα小鼠在 Z-核酸结合 (Zα) 结构域中具有两个点突变，可消除 Z-RNA 结合，在包括肺在内的多个器官中表现出 I 型干扰素 (IFN) 的自发诱导，其中两个和造血细胞显示干扰素刺激基因（ISG）诱导。肺中性粒细胞表达由转录因子 IRF3 诱导的 ISG，表明中性粒细胞在这种 IFN 反应中起起始作用。Adar1 ^mZα/mZα中的干扰素反应小鼠需要适配器 MAVS，这意味着细胞溶质 RNA 传感。腺苷到肌苷的变化富含转座因子，并揭示了 ADAR1 的 Zα 结构域在编辑 RNA 子集时的特定要求。因此，Z 构象的内源性 RNA 具有被 ADAR1 削弱的免疫刺激潜力，与人类自身炎症性疾病有关。