Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China.
Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
J Immunol. 2023 Jul 1;211(1):130-139. doi: 10.4049/jimmunol.2300033.
Methyltransferase (METTL3), the most important N6-methyladenosine (m6A) writer, plays a vital role in regulating immune-related signaling pathways. However, the underlying mechanism of METTL3 action remains largely unknown, especially in lower vertebrates. The results of this study show that METTL3 inhibits innate immune response and promotes the infection of miiuy croaker, Miichthys miiuy, by Siniperca chuatsi rhabdovirus and Vibrio anguillarum. Significantly, the function of METTL3 in inhibiting immunity depends on its methylase activity. Mechanistically, METTL3 increases the methylation level of trif and myd88 mRNA, rendering them sensitive to degradation by the YTHDF2/3 reader proteins. By contrast, we found that the YTHDF1 reader protein promotes the translation of myd88 mRNA. In summary, these results indicate that METTL3-mediated m6A modification of trif and myd88 mRNAs suppresses innate immunity by inhibiting the TLR pathway, unveiling a molecular mechanism by which RNA methylation controls innate immunity to pathogens in the teleost fish.
甲基转移酶（METTL3）是最重要的 N6-甲基腺苷（m6A）写入器，在调节免疫相关信号通路方面发挥着重要作用。然而，METTL3 作用的潜在机制在很大程度上仍然未知，特别是在低等脊椎动物中。本研究结果表明，METTL3 抑制先天免疫反应，并促进黄颡鱼感染虹彩病毒和鳗弧菌。值得注意的是，METTL3 抑制免疫的功能依赖于其甲基转移酶活性。在机制上，METTL3 增加了 trif 和 myd88 mRNA 的甲基化水平，使它们容易被 YTHDF2/3 读取蛋白降解。相比之下，我们发现 YTHDF1 读取蛋白促进了 myd88 mRNA 的翻译。总之，这些结果表明，METTL3 介导的 trif 和 myd88 mRNA 的 m6A 修饰通过抑制 TLR 通路抑制先天免疫，揭示了 RNA 甲基化控制硬骨鱼对病原体先天免疫的分子机制。
