Type I interferon (IFN) is produced when host sensors detect foreign nucleic acids, but how sensors differentiate self from nonself nucleic acids, such as double-stranded RNA (dsRNA), is incompletely understood. Mutations in ADAR1, an adenosine-to-inosine editing enzyme of dsRNA, cause Aicardi-Goutières syndrome, an autoinflammatory disorder associated with spontaneous interferon production and neurologic sequelae. We generated ADAR1 knockout human cells to explore ADAR1 substrates and function. ADAR1 primarily edited Alu elements in RNA polymerase II (pol II)-transcribed mRNAs, but not putative pol III-transcribed Alus. During the IFN response, ADAR1 blocked translational shutdown by inhibiting hyperactivation of PKR, a dsRNA sensor. ADAR1 dsRNA binding and catalytic activities were required to fully prevent endogenous RNA from activating PKR. Remarkably, ADAR1 knockout neuronal progenitor cells exhibited MDA5 (dsRNA sensor)-dependent spontaneous interferon production, PKR activation, and cell death. Thus, human ADAR1 regulates sensing of self versus nonself RNA, allowing pathogen detection while avoiding autoinflammation.

中文翻译：

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人类ADAR1阻止内源性RNA触发翻译关闭。

当宿主传感器检测到异源核酸时会产生I型干扰素（IFN），但对传感器如何将自身与非自身核酸（例如双链RNA（dsRNA））区分开的了解还不够。dsRNA的腺苷到肌苷编辑酶ADAR1中的突变会引起Aicardi-Goutières综合征，这是一种与自发干扰素产生和神经系统后遗症相关的自身炎症性疾病。我们生成了ADAR1基因敲除人类细胞，以探索ADAR1底物和功能。ADAR1主要编辑RNA聚合酶II（pol II）转录的mRNA中的Alu元件，但不编辑推定的pol III转录的Alus。在IFN反应期间，ADAR1通过抑制dsRNA传感器PKR的过度激活来阻止翻译关闭。要完全防止内源性RNA激活PKR，需要ADAR1 dsRNA的结合和催化活性。值得注意的是，ADAR1基因敲除的神经元祖细胞表现出MDA5（dsRNA传感器）依赖的自发干扰素产生，PKR激活和细胞死亡。因此，人类ADAR1调节自身与非自身RNA的感应，从而可以检测病原体，同时避免自身炎症。