Disruption of Z-RNA–binding of ADAR1 induces Aicardi-Goutières syndrome–like encephalopathy in mice
Disruption of Z-RNA–binding of ADAR1 induces Aicardi-Goutières syndrome–like encephalopathy in mice
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DOI：
10.1101/2020.12.16.422984
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发表时间：
2020-12
期刊：
影响因子：
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通讯作者：
T. Nakahama;Yuki Kato;T. Shibuya;Jung In Kim;Tuangtong Vongpipatana;Hiroyuki Todo;Yanfang Xing;Y. Kawahara
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文献类型：
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作者：
T. Nakahama;Yuki Kato;T. Shibuya;Jung In Kim;Tuangtong Vongpipatana;Hiroyuki Todo;Yanfang Xing;Y. Kawahara
ADAR 1 p150是一种负责腺苷到肌苷RNA编辑的酶。ADAR 1 p150的缺失导致胚胎死亡，I型干扰素（IFN）签名，由异常的MDA 5感应未编辑的转录物引起。ADAR 1 p150含有一个独特的Z-DNA/RNA结合结构域α（Zα）;然而，该结构域的作用尚不清楚。在Aicardi-Goutières综合征（AGS）（一种遗传性干扰素病）患者中已发现该结构域的突变，这表明在避免MDA 5激活方面发挥重要作用。在这里，我们通过比较Adar 1/Adar 2敲除细胞中表达的野生型和突变亚型之间的活性，表明Zα结构域中的突变降低了ADAR 1 p150的编辑活性。此外，我们创建了Zα结构域突变的敲入小鼠，这些小鼠表现出严重的生长迟缓和器官发育异常，包括具有I型IFN特征的AGS样脑病。这些异常通过同时缺失MDA 5而得到改善。总的来说，Z-RNA识别有助于ADAR 1 p150介导的RNA编辑，从而阻止MDA 5激活。
ADAR1 p150 is an enzyme responsible for adenosine-to-inosine RNA editing. Deletion of ADAR1 p150 results in embryonic lethality with a type I interferon (IFN) signature, caused by aberrant MDA5 sensing unedited transcripts. ADAR1 p150 contains a unique Z-DNA/RNA–binding domain α (Zα); however, the role of this domain remains unknown. A mutation has been identified in this domain in patients with Aicardi-Goutières syndrome (AGS), an inherited interferonopathy, suggesting an essential role in avoiding MDA5 activation. Here, we show that a mutation in the Zα domain reduces the editing activity of ADAR1 p150 by comparing activity between wild-type and mutated isoforms expressed in Adar1/Adar2 knockout cells. Furthermore, we created Zα domain–mutated knock-in mice, which displayed severe growth retardation with abnormal organ development, including AGS-like encephalopathy with a type I IFN signature. These abnormalities were ameliorated by the concurrent deletion of MDA5. Collectively, Z-RNA–recognition contributes to ADAR1 p150–mediated RNA editing, which prevents MDA5 activation.