The RNA editing enzyme ADAR1 is a key regulatory of innate immune responses to RNA

The ADAR RNA editing enzymes deaminate adenosine bases to inosines in cellular RNAs, recoding open reading frames. Human ADAR1 mutations cause Aicardi-Goutieres Syndrome (AGS) and Adar1 mutant mice showing an aberrant interferon response and death by embryonic day E12.5 model the human disease. Searches have not identified key ADAR1 RNA editing sites recoding immune/haematopoietic proteins but editing is widespread in Alu sequences. We show that Adar1 embryonic lethality is rescued in Adar1; Mavs double mutant mice in which general antiviral responses to cytoplasmic dsRNA are prevented. We propose that inosine bases are epigenetic marks identifying cellular RNA as innate immune "self." Consistent with this idea we show that an editing-active cytoplasmic ADAR is required to prevent aberrant immune responses in Adar1 mutant mouse embryo fibroblasts. No dramatic increase in repetitive transcripts is observed. AGS mutations in ADAR1 affect editing by the interferon-inducible cytoplasmic ADAR1 isoform. RNA-seq expression profiling in Adar1 and Adar1/Mavs knockout mice embryos.ADAR RNA编辑酶（ADAR RNA editing enzymes）可将细胞RNA中的腺苷碱基脱氨为肌苷，进而重编码开放阅读框（open reading frames）。人类ADAR1基因突变可引发艾卡迪-古特雷斯综合征（Aicardi-Goutieres Syndrome, AGS）；Adar1突变小鼠会出现异常干扰素应答，并于胚胎第12.5天（E12.5）死亡，该小鼠模型可模拟人类疾病。目前尚未发现可重编码免疫/造血蛋白的关键ADAR1 RNA编辑位点，但Alu序列（Alu sequences）中广泛存在RNA编辑现象。本研究证实，Adar1突变导致的胚胎致死可在Adar1; Mavs双突变小鼠中得到挽救——这类小鼠可阻断对细胞质双链RNA的一般性抗病毒应答。我们提出假说：肌苷碱基可作为表观遗传标记，将细胞RNA识别为先天免疫的‘自身’成分。该假说与下述实验结果一致：具备编辑活性的细胞质ADAR是阻止Adar1突变小鼠胚胎成纤维细胞出现异常免疫应答的必要条件。未观察到重复转录本出现显著上调。ADAR1上的AGS致病突变会影响干扰素诱导型细胞质ADAR1亚型的编辑功能。本研究对Adar1敲除及Adar1/Mavs敲除小鼠胚胎开展了RNA测序（RNA-seq）表达谱分析。