Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota, United States of America.
PLoS Biol. 2018 Nov 29;16(11):e2006577. doi: 10.1371/journal.pbio.2006577. eCollection 2018 Nov.
The interferon (IFN)-mediated innate immune response is the first line of defense against viruses. However, an IFN-stimulated gene, the adenosine deaminase acting on RNA 1 (ADAR1), favors the replication of several viruses. ADAR1 binds double-stranded RNA and converts adenosine to inosine by deamination. This form of editing makes duplex RNA unstable, thereby preventing IFN induction. To better understand how ADAR1 works at the cellular level, we generated cell lines that express exclusively either the IFN-inducible, cytoplasmic isoform ADAR1p150, the constitutively expressed nuclear isoform ADAR1p110, or no isoform. By comparing the transcriptome of these cell lines, we identified more than 150 polymerase II transcripts that are extensively edited, and we attributed most editing events to ADAR1p150. Editing is focused on inverted transposable elements, located mainly within introns and untranslated regions, and predicted to form duplex RNA structures. Editing of these elements occurs also in primary human samples, and there is evidence for cross-species evolutionary conservation of editing patterns in primates and, to a lesser extent, in rodents. Whereas ADAR1p150 rarely edits tightly encapsidated standard measles virus (MeV) genomes, it efficiently edits genomes with inverted repeats accidentally generated by a mutant MeV. We also show that immune activation occurs in fully ADAR1-deficient (ADAR1KO) cells, restricting virus growth, and that complementation of these cells with ADAR1p150 rescues virus growth and suppresses innate immunity activation. Finally, by knocking out either protein kinase R (PKR) or mitochondrial antiviral signaling protein (MAVS)-another protein controlling the response to duplex RNA-in ADAR1KO cells, we show that PKR activation elicits a stronger antiviral response. Thus, ADAR1 prevents innate immunity activation by cellular transcripts that include extensive duplex RNA structures. The trade-off is that viruses take advantage of ADAR1 to elude innate immunity control.
干扰素（IFN）介导的先天免疫反应是抵抗病毒的第一道防线。然而，一种 IFN 刺激基因，即腺苷脱氨酶作用于 RNA 1（ADAR1），有利于几种病毒的复制。ADAR1 结合双链 RNA 并通过脱氨作用将腺苷转化为肌苷。这种编辑形式使双链 RNA 不稳定，从而阻止 IFN 诱导。为了更好地了解 ADAR1 在细胞水平上的工作机制，我们生成了仅表达 IFN 诱导的细胞质同工型 ADAR1p150、组成型表达的核同工型 ADAR1p110 或无同工型的细胞系。通过比较这些细胞系的转录组，我们鉴定出 150 多个广泛编辑的聚合酶 II 转录本，并且我们将大多数编辑事件归因于 ADAR1p150。编辑集中在反转录转座子上，主要位于内含子和非翻译区，并且预测形成双链 RNA 结构。这些元件的编辑也发生在原代人类样本中，并且在灵长类动物和在较小程度上在啮齿动物中存在编辑模式的跨物种进化保守性的证据。尽管 ADAR1p150 很少编辑紧密包裹的标准麻疹病毒（MeV）基因组，但它有效地编辑了由突变 MeV 意外产生的反向重复基因组。我们还表明，完全缺乏 ADAR1（ADAR1KO）的细胞中会发生免疫激活，限制病毒生长，并且用 ADAR1p150 补充这些细胞可挽救病毒生长并抑制先天免疫激活。最后，通过敲除蛋白激酶 R（PKR）或线粒体抗病毒信号蛋白（MAVS）-另一种控制双链 RNA 反应的蛋白-在 ADAR1KO 细胞中，我们表明 PKR 激活引发更强的抗病毒反应。因此，ADAR1 通过包括广泛双链 RNA 结构的细胞转录本来防止先天免疫激活。权衡的结果是，病毒利用 ADAR1 逃避先天免疫控制。
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