Department of Genetics, Stanford University, Stanford, CA 94305, USA.
St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia; Department of Medicine, Eastern Hill Precinct, Melbourne Medical School, University of Melbourne, Fitzroy, VIC 3065, Australia.
Mol Cell. 2023 Nov 2;83(21):3869-3884.e7. doi: 10.1016/j.molcel.2023.09.018. Epub 2023 Oct 4.
Effective immunity requires the innate immune system to distinguish foreign nucleic acids from cellular ones. Cellular double-stranded RNAs (dsRNAs) are edited by the RNA-editing enzyme ADAR1 to evade being recognized as viral dsRNA by cytoplasmic dsRNA sensors, including MDA5 and PKR. The loss of ADAR1-mediated RNA editing of cellular dsRNA activates MDA5. 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, whereas 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 Adar1p150 mice to adulthood, contrasting with the limited or no rescue by removing MDA5 or PKR alone. Our findings demonstrate that MDA5 and PKR are the primary in vivo 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核酸与细胞内核酸区分开来。细胞双链 RNA（dsRNA）被 RNA 编辑酶 ADAR1 编辑，以逃避被细胞质 dsRNA 传感器（包括 MDA5 和 PKR）识别为病毒 dsRNA。ADAR1 介导的细胞 dsRNA 的 RNA 编辑缺失会激活 MDA5。已经提出了 ADAR1 的其他非 RNA 编辑依赖的功能，但尚未阐明具体的机制。我们现在证明 ADAR1 介导的 RNA 编辑缺失特异性地激活 MDA5，而细胞质 ADAR1p150 同工型或其 dsRNA 结合活性的缺失则能够激活 PKR。删除 MDA5 和 PKR 两者都可以使 Adar1p150 小鼠的胚胎致死率完全恢复到成年，与单独删除 MDA5 或 PKR 时的有限或没有恢复形成对比。我们的研究结果表明，MDA5 和 PKR 是 ADAR1p150 缺失后致命自身炎症的主要体内效应物。
