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

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 autoreactivity in humans and mice, thus serving as a therapeutic target in systemic autoimmunity.