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N 6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling.
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2020-09-11 , DOI: 10.1074/jbc.ra120.014260
Geon-Woo Kim 1 , Hasan Imam 1 , Mohsin Khan 1 , Aleem Siddiqui 1
Affiliation  

N6-Methyladenosine (m6A), the methylation of the adenosine base at the nitrogen 6 position, is the most common epitranscriptomic modification of mRNA that affects a wide variety of biological functions. We have previously reported that hepatitis B viral RNAs are m6A-modified, displaying a dual functional role in the viral life cycle. Here, we show that cellular m6A machinery regulates host innate immunity against hepatitis B and C viral infections by inducing m6A modification of viral transcripts. The depletion of the m6A writer enzymes (METTL3 and METTL14) leads to an increase in viral RNA recognition by retinoic acid–inducible gene I (RIG-I), thereby stimulating type I interferon production. This is reversed in cells in which m6A METTL3 and METTL14 are overexpressed. The m6A modification of viral RNAs renders RIG-I signaling less effective, whereas single nucleotide mutation of m6A consensus motif of viral RNAs enhances RIG-I sensing activity. Importantly, m6A reader proteins (YTHDF2 and YTHDF3) inhibit RIG-I–transduced signaling activated by viral RNAs by occupying m6A-modified RNAs and inhibiting RIG-I recognition. Collectively, our results provide new insights into the mechanism of immune evasion via m6A modification of viral RNAs.

中文翻译:


乙型肝炎和丙型肝炎病毒 RNA 的 N 6-甲基腺苷修饰通过 RIG-I 信号传导减弱宿主先天免疫力。



N6-甲基腺苷 (m6A) 是氮 6 位腺苷碱基的甲基化,是影响多种生物学功能的最常见的 mRNA 表观转录组修饰。我们之前报道过乙型肝炎病毒 RNA 经过 m6A 修饰,在病毒生命周期中表现出双重功能作用。在这里,我们证明细胞 m6A 机制通过诱导病毒转录本的 m6A 修饰来调节宿主针对乙型肝炎和丙型肝炎病毒感染的先天免疫。 m6A 写入酶(METTL3 和 METTL14)的消耗导致视黄酸诱导基因 I (RIG-I) 对病毒 RNA 的识别增加,从而刺激 I 型干扰素的产生。在 m6A METTL3 和 METTL14 过表达的细胞中,情况相反。病毒RNA的m6A修饰使RIG-I信号传导效率降低,而病毒RNA的m6A共有基序的单核苷酸突变增强了RIG-I传感活性。重要的是,m6A 阅读器蛋白(YTHDF2 和 YTHDF3)通过占据 m6A 修饰的 RNA 并抑制 RIG-I 识别来抑制由病毒 RNA 激活的 RIG-I 转导信号。总的来说,我们的结果为通过病毒 RNA 的 m6A 修饰进行免疫逃避的机制提供了新的见解。
更新日期:2020-09-11
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