Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA.
Division of Genetics, Program in Immunology, Institute for Genomic Medicine, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive MC 0762, La Jolla, CA 92093, USA; Bioinformatics Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cell Rep. 2021 May 11;35(6):109091. doi: 10.1016/j.celrep.2021.109091. Epub 2021 May 3.
It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlining molecular mechanism. N-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigate m6A modification of the SARS-CoV-2 gene in regulating the host cell innate immune response. Our data show that the SARS-CoV-2 virus has m6A modifications that are enriched in the 3' end of the viral genome. We find that depletion of the host cell m6A methyltransferase METTL3 decreases m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increases RIG-I binding and subsequently enhances the downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in patients with severe coronavirus disease 2019 (COVID-19). These findings will aid in the understanding of COVID-19 pathogenesis and the design of future studies regulating innate immunity for COVID-19 treatment.
了解广泛存在的严重急性呼吸综合征冠状病毒 2 型（SARS-CoV-2）与宿主免疫反应的关系，并研究其潜在的分子机制迫在眉睫。RNA 中的腺苷 N-甲基化（m6A）调节许多生理和疾病过程。在这里，我们研究了 SARS-CoV-2 基因中的 m6A 修饰在调节宿主细胞固有免疫反应中的作用。我们的数据表明，SARS-CoV-2 病毒具有 m6A 修饰，这些修饰在病毒基因组的 3'端富集。我们发现，耗尽宿主细胞的 m6A 甲基转移酶 METTL3 会降低 SARS-CoV-2 和宿主基因中的 m6A 水平，而病毒 RNA 中的 m6A 减少会增加 RIG-I 的结合，进而增强下游固有免疫信号通路和炎症基因的表达。在患有严重 2019 年冠状病毒病（COVID-19）的患者中，METTL3 的表达减少和炎症基因被诱导。这些发现将有助于理解 COVID-19 的发病机制，并为未来调节 COVID-19 治疗中固有免疫的研究提供设计思路。
