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

Shuyi Wang, Hui Han, Yichao Qian, Xinyuan Ruan, Zhangmei Lin, Jin Li, Binfeng Chen, Yimei Lai, Zhaoyu Wang, Mengyuan Li, Jingping Wen, Xiaoyu Yin, Niansheng Yang, Shuibin Lin and Hui Zhang ()
Additional contact information
Shuyi Wang: Sun Yat-sen University
Hui Han: Sun Yat-sen University
Yichao Qian: Sun Yat-sen University
Xinyuan Ruan: Sun Yat-sen University
Zhangmei Lin: Sun Yat-sen University
Jin Li: Sun Yat-sen University
Binfeng Chen: Sun Yat-sen University
Yimei Lai: Sun Yat-sen University
Zhaoyu Wang: Sun Yat-sen University
Mengyuan Li: Sun Yat-sen University
Jingping Wen: Sun Yat-sen University
Xiaoyu Yin: Sun Yat-sen University
Niansheng Yang: Sun Yat-sen University
Shuibin Lin: Sun Yat-sen University
Hui Zhang: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54941-4

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