Aberrant METTL1-mediated tRNA m7G modification alters B-cell responses in systemic autoimmunity in humans and mice

作者：Shuyi Wang, Hui Han, Yichao Qian, Xinyuan Ruan, Zhangmei Lin, Jin Li, Binfeng Chen, Yimei Lai, Zhaoyu Wang, Mengyuan Li, Jing Wen, Xiaoyu Yin, Niansheng Yang, Shuibin Lin, Hui Zhang · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-54941-4 · 被引用次数：9 · 研究领域：RNA modifications and cancer、interferon and immune responses、Cancer-related molecular mechanisms research

Upon activation, naive B cells exit their quiescent state and enter germinal center (GC) responses, a transition accompanied by increased protein synthesis. How protein translation efficiency is adequately adjusted to meet the increased demand requires further investigation. Here, we identify the methyltransferase METTL1 as a translational checkpoint during GC responses. Conditional knockout of Mettl1 in mouse B cells blocks GC entry and impairs GC formation, whereas conditional knock-in of Mettl1 promotes GC responses. Mechanistically, METTL1 catalyzes m7G modification in a specific subset of tRNAs to preferentially translate BCR signaling-related proteins, ensuring mitochondrial electron transporter chain activity and sufficient bioenergetics in B cells. Pathologically, METTL1-mediated tRNA m7G modification controls B-cell autoreactivity in SLE patients or lupus-prone mice, and deletion of Mettl1 alleviates dysregulated B-cell responses during autoimmune induction. Thus, these results support the function of METTL1 in orchestrating an effective B-cell response and reveal that aberrant METTL1-mediated tRNA m7G modification promotes autoreactive B cells in systemic autoimmunity. An effective B cell response requires a rapid increase in protein synthesis. Using multi-omics approaches, here the authors show that the methyltransferase METTL1 drives B cell activation via the tRNA m7G modification-dependent translation of BCR signaling and that aberrant METTL1 causes B cell autore...