Mutations in the adenosine-to-inosine RNA-editing enzyme ADAR1 p150, including point mutations in the Z-RNA recognition domain Zα, are associated with Aicardi-Goutières syndrome (AGS). Here, we examined the in vivo relevance of ADAR1 binding of Z-RNA. Mutation of W197 in Zα, which abolished Z-RNA binding, reduced RNA editing. Adar1^W197A/W197A mice displayed severe growth retardation after birth, broad expression of interferon-stimulated genes (ISGs), and abnormal development of multiple organs. Notably, malformation of the brain was accompanied by white matter vacuolation and gliosis, reminiscent of AGS-associated encephalopathy. Concurrent deletion of the double-stranded RNA sensor MDA5 ameliorated these abnormalities. ADAR1 (W197A) expression increased in a feedback manner downstream of type I interferons, resulting in increased RNA editing at a subset of, but not all, ADAR1 target sites. This increased expression did not ameliorate inflammation in Adar1^W197A/W197A mice. Thus, editing of select endogenous RNAs by ADAR1 is essential for preventing inappropriate MDA5-mediated inflammation, with relevance to the pathogenesis of AGS.

腺苷转肌苷 RNA 编辑酶 ADAR1 p150 的突变，包括 Z-RNA 识别域 Zα 中的点突变，与 Aicardi-Goutières 综合征 (AGS) 相关。在这里，我们检查了ADAR1 与 Z-RNA 结合的体内相关性。Zα 中 W197 的突变消除了 Z-RNA 结合，减少了 RNA 编辑。Adar1 ^W197A/W197A小鼠出生后表现出严重的生长迟缓、干扰素刺激基因 (ISG) 的广泛表达和多器官发育异常。值得注意的是，大脑畸形伴有白质空泡化和神经胶质增生，让人联想到 AGS 相关脑病。双链RNA传感器MDA5的同时缺失改善了这些异常。ADAR1 (W197A) 表达在 I 型干扰素下游以反馈方式增加，导致 ADAR1 靶点子集（但不是全部）的 RNA 编辑增加。这种增加的表达并没有改善Adar1 ^W197A/W197A小鼠的炎症。因此，通过 ADAR1 编辑选择的内源性 RNA 对于预防不适当的 MDA5 介导的炎症至关重要，这与 AGS 的发病机制有关。