Hu Shi-Bin, Heraud-Farlow Jacki, Sun Tao, Liang Zhen, Goradia Ankita, Taylor Scott, Walkley Carl R, Li Jin Billy
bioRxiv. 2023 Jan 25:2023.01.25.525475. doi: 10.1101/2023.01.25.525475.
Effective immunity requires the innate immune system to distinguish foreign (non-self) nucleic acids from cellular (self) nucleic acids. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA editing enzyme ADAR1 to prevent their dsRNA structure pattern being recognized as viral dsRNA by cytoplasmic dsRNA sensors including MDA5, PKR and ZBP1. A loss of ADAR1-mediated RNA editing of cellular dsRNA activates MDA5. However, additional RNA editing-independent functions of ADAR1 have been proposed, but a specific mechanism has not been delineated. We now demonstrate that the loss of ADAR1-mediated RNA editing specifically activates MDA5, while loss of the cytoplasmic ADAR1p150 isoform or its dsRNA binding activity enabled PKR activation. Deleting both MDA5 and PKR resulted in complete rescue of the embryonic lethality of mice to adulthood, contrasting with the limited or no rescue by removing MDA5, PKR or ZBP1 alone, demonstrating that this is a species conserved function of ADAR1p150. Our findings demonstrate that MDA5 and PKR are the primary effectors of fatal autoinflammation following the loss of ADAR1p150.
有效的免疫需要先天免疫系统将外来（非自身）核酸与细胞（自身）核酸区分开来。细胞双链RNA（dsRNA）由RNA编辑酶ADAR1进行编辑，以防止其dsRNA结构模式被包括MDA5、PKR和ZBP1在内的细胞质dsRNA传感器识别为病毒dsRNA。ADAR1介导的细胞dsRNA的RNA编辑缺失会激活MDA5。然而，有人提出了ADAR1的其他与RNA编辑无关的功能，但具体机制尚未阐明。我们现在证明，ADAR1介导的RNA编辑缺失会特异性激活MDA5，而细胞质ADAR1p150异构体的缺失或其dsRNA结合活性会使PKR激活。删除MDA5和PKR可使小鼠胚胎致死率完全恢复至成年期，这与单独去除MDA5、PKR或ZBP1导致的有限恢复或无恢复形成对比，表明这是ADAR1p150的一种物种保守功能。我们的研究结果表明，MDA5和PKR是ADAR1p150缺失后致命性自身炎症的主要效应因子。
