The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.
The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.
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DOI：
10.1016/j.celrep.2014.10.041
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发表时间：
2014-11-20
期刊：
影响因子：
8.8
通讯作者：
O'Connell MA
中科院分区：
文献类型：
--
作者：
Mannion NM;Greenwood SM;Young R;Cox S;Brindle J;Read D;Nellåker C;Vesely C;Ponting CP;McLaughlin PJ;Jantsch MF;Dorin J;Adams IR;Scadden AD;Ohman M;Keegan LP;O'Connell MA
ADAR RNA编辑酶将细胞RNA中的腺苷碱基脱氨基为肌苷。在ADAR1突变导致艾卡迪-古蒂埃综合征(AGS)或纹状体神经变性引起的肌张力障碍的患者中，会发生干扰素的异常表达。ADAR1突变小鼠胚胎表现出异常的干扰素诱导，并在胚胎E12.5天死亡。我们证明了ADAR1对胚胎的致死性在ADAR1中被挽救到活着出生；在MAVS双重突变体中，抗病毒干扰素对细胞质双链RNA(DsRNA)的诱导反应被阻止。通过恢复编辑活性胞质ADAR的表达，ADAR1突变小鼠胚胎成纤维细胞的异常免疫反应显著减少。我们认为，细胞RNA中的肌苷通过改变RLR的相互作用来抑制抗病毒、炎症和干扰素反应。将含有肌苷-尿嘧啶碱基对的dsRNA寡核苷酸导入ADAR1突变的小鼠胚胎成纤维细胞，可减少异常的先天免疫反应。引起AGS的ADAR1突变对干扰素诱导的细胞质异构体活性的影响比对核异构体的影响更严重。ADAR1突变的小鼠胚胎致死性在ADAR1中被挽救；MAVS的双重突变在ADAR1突变中的抗病毒反应异常是由于RNA的丢失编辑人类ADAR1突变引起的AGS主要影响干扰素诱导的亚型我们认为肌苷有助于天然免疫来区分细胞和病毒RNA缺乏ADAR1的小鼠有增强的免疫反应和应激相关的细胞凋亡。Mannion等人。证明这种突变可以通过产生带有MAVS(一种先天性免疫基因)的双重突变而被挽救到出生，这表明ADAR1在先天性免疫中发挥着核心作用。
The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform. Adar1 mutant mouse embryonic lethality is rescued in Adar1; Mavs double mutants Aberrant antiviral responses in the Adar1 mutant are due to loss of RNA editing Human ADAR1 mutations causing AGS affect primarily the interferon-inducible isoform We propose that inosine helps innate immunity to distinguish cellular from viral RNA Mice lacking Adar1 have a heightened immune response and stress-related apoptosis. Mannion et al. demonstrate that this mutation can be rescued to birth by generating a double mutant with Mavs, an innate immune gene, indicating the central role ADAR1 plays in innate immunity.