N6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling
N6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling
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DOI：
10.1074/jbc.ra120.014260
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发表时间：
2020-09-11
影响因子：
4.8
通讯作者：
Siddiqui, Aleem
中科院分区：
文献类型：
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作者：
Kim, Geon-Woo;Imam, Hasan;Siddiqui, Aleem
N-6-甲基腺苷（m（6）A）是腺苷碱基在氮6位的甲基化，是mRNA最常见的表位转录修饰，影响多种生物学功能。我们以前曾报道过，B型肝炎病毒RNA是m（6）A修饰的，在病毒生命周期中显示出双重功能作用。在这里，我们表明，细胞m（6）A机制调节宿主先天免疫对B和C型肝炎病毒感染诱导m（6）A修饰的病毒转录。m（6）A写入酶（胃L3和胃L14）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。这在m（6）A胃L3和胃L14过表达的细胞中是相反的。病毒RNA的m（6）A修饰使RIG-I信号传导不那么有效，而病毒RNA的m（6）A共有基序的单核苷酸突变增强RIG-I传感活性。重要的是，m（6）A阅读蛋白（YTHDF 2和YTHDF 3）通过占据m（6）A修饰的RNA并抑制RIG-I识别来抑制由病毒RNA激活的RIG-I转导的信号传导。总的来说，我们的结果提供了新的见解免疫逃避机制通过m（6）A修饰的病毒RNA。
N-6-Methyladenosine (m(6)A), 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 m(6)A-modified, displaying a dual functional role in the viral life cycle. Here, we show that cellular m(6)A machinery regulates host innate immunity against hepatitis B and C viral infections by inducing m(6)A modification of viral transcripts. The depletion of the m(6)A 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 m(6)A METTL3 and METTL14 are overexpressed. The m(6)A modification of viral RNAs renders RIG-I signaling less effective, whereas single nucleotide mutation of m(6)A consensus motif of viral RNAs enhances RIG-I sensing activity. Importantly, m(6)A reader proteins (YTHDF2 and YTHDF3) inhibit RIG-I-transduced signaling activated by viral RNAs by occupying m(6)A-modified RNAs and inhibiting RIG-I recognition. Collectively, our results provide new insights into the mechanism of immune evasion via m(6)A modification of viral RNAs.