<br>ADAR1 进行的 RNA 编辑可防止 MDA5 将内源 dsRNA 视为非自身,Science

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ADAR1 进行的 RNA 编辑可防止 MDA5 将内源 dsRNA 视为非自身
Science ( IF 44.7 ) Pub Date : 2015-07-23 , DOI: 10.1126/science.aac7049
Brian J Liddicoat ₁ , Robert Piskol ₂ , Alistair M Chalk ₁ , Gokul Ramaswami ₂ , Miyoko Higuchi ₃ , Jochen C Hartner ₄ , Jin Billy Li ₂ , Peter H Seeburg ₃ , Carl R Walkley ₁

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RNA 编辑有助于识别细胞 RNA 信使 RNA (mRNA) 中的腺苷碱基可以通过酶促修饰并转变为肌苷碱基。这种 RNA“编辑”是由作用于 RNA (ADAR) 酶的腺苷脱氨酶介导的。李迪克等人。研究表明，主要编辑酶 ADAR1 的体内靶标是细胞 mRNA 非编码部分中的长双链 RNA (dsRNA) 结构。 ADAR1 定向编辑这些细胞靶标对于避免激活细胞质中 dsRNA 的免疫反应至关重要，因为 dsRNA 也是病毒感染的标志物。科学，本期第 14 页。第 1115 章腺苷至肌苷 (A-to-I) 编辑是一种非常普遍的 RNA 转录后修饰，由 ADAR（作用于 RNA 的腺苷脱氨酶）酶介导。除了 RNA 编辑之外，ADAR1 还提出了其他功能。为了确定 ADAR1 对 RNA 编辑的具体作用，我们生成了具有编辑缺陷敲入突变的小鼠（Adar1E861A，其中 E861A 表示 Glu861→Ala861）。 Adar1E861A/E861A 胚胎在 ~E13.5（胚胎第 13.5 天）死亡，具有激活的干扰素和双链 RNA (dsRNA) 传感途径。对 ADAR1 体内底物的全基因组分析发现，内源转录物 3' 非翻译区内的长 dsRNA 茎环内存在聚集性超编辑。最后，通过同时删除 dsRNA 胞质传感器 MDA5，挽救了 Adar1E861A/E861A 的胚胎死亡和表型。内源 dsRNA 的 A-to-I 编辑是 ADAR1 的基本功能，可防止内源转录物激活胞质 dsRNA 反应。

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RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself

RNA editing helps identify cellular RNAs Adenosine bases in messenger RNA (mRNAs) can be enzymatically modified and changed into inosine bases. This RNA “editing” is mediated by adenosine deaminase acting on RNA (ADAR) enzymes. Liddicoat et al. show that the in vivo targets of the principal editing enzyme, ADAR1, are long double-stranded RNA (dsRNA) structures in noncoding portions of cellular mRNAs. ADAR1-directed editing of these cellular targets is critical to avoid activation of an immune response to dsRNA in the cytoplasm, because dsRNA is also a marker of viral infection. Science, this issue p. 1115 The principal RNA-editing enzyme modifies cellular RNAs to prevent their erroneous identification as foreign RNA. Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1E861A, where E861A denotes Glu861→Ala861). Adar1E861A/E861A embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)–sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3′ untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1E861A/E861A were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.

更新日期：2015-07-23

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