Aberrant METTL1-mediated tRNA m 7 G modification alters B-cell responses in systemic autoimmunity in humans and mice.

Autor: Wang S; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Han H; Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Qian Y; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.; Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Ruan X; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Lin Z; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Li J; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Chen B; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Lai Y; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Wang Z; Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Li M; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Wen J; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Yin X; Department of Pancreato-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Yang N; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Lin S; Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.; Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China., Zhang H; Department of Rheumatology and Clinical Immunology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. zhangh656@mail.sysu.edu.cn.; Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China. zhangh656@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Dec 05; Vol. 15 (1), pp. 10599. Date of Electronic Publication: 2024 Dec 05.
DOI: 10.1038/s41467-024-54941-4
Abstrakt: 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 m 7 G 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 m 7 G 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 m 7 G modification promotes autoreactive B cells in systemic autoimmunity.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE