Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutieres-syndrome-like encephalopathy
Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutieres-syndrome-like encephalopathy
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DOI：
10.1016/j.immuni.2021.08.022
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发表时间：
2021-09-14
期刊：
影响因子：
32.4
通讯作者：
Kawahara, Yukio
中科院分区：
文献类型：
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作者：
Nakahama, Taisuke;Kato, Yuki;Kawahara, Yukio
腺苷-肌苷rna编辑酶ADAR1 p150的突变，包括Z- rna识别结构域Z α的点突变，与Aicardi-Goutieres综合征（AGS）有关。在这里，我们研究了ADAR1与Z-RNA结合的体内相关性。W197在Z α中的突变，破坏了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（ISGs）广泛表达，多器官发育异常。值得注意的是，脑畸形伴有白质空泡化和神经胶质瘤，令人联想到ags相关的脑病。同时删除双链RNA传感器MDA5可改善这些异常。ADAR1 （W197A）在I型干扰素下游以反馈方式表达增加，导致ADAR1靶位点的一部分（但不是全部）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，ADAR1编辑选择的内源性rna对于预防不当的mda5介导的炎症至关重要，这与AGS的发病机制有关。
Mutations in the adenosine-to-inosine RNA-editing enzyme ADAR1 p150, including point mutations in the Z-RNA recognition domain Z alpha, are associated with Aicardi-Goutieres syndrome (AGS). Here, we examined the in vivo relevance of ADAR1 binding of Z-RNA. Mutation of W197 in Z alpha, 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 inflammationin 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.