MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation

Wenna Chi, Na Kang, Linlin Sheng, Sichen Liu, Lei Tao, Xizhi Cao, Ye Liu, Can Zhu, Yuming Zhang, Bolong Wu, Ruiqun Chen, Lili Cheng, Jing Wang, Xiaolin Sun, Xiaohui Liu, Haiteng Deng, Jinliang Yang, Zhanguo Li, Wanli Liu () and Ligong Chen ()
Additional contact information
Wenna Chi: Tsinghua University
Na Kang: Tsinghua University
Linlin Sheng: Tsinghua University
Sichen Liu: Tsinghua University
Lei Tao: Tsinghua University
Xizhi Cao: Tsinghua University
Ye Liu: Tsinghua University
Can Zhu: Tsinghua University
Yuming Zhang: Tsinghua University
Bolong Wu: Tsinghua University
Ruiqun Chen: Tsinghua University
Lili Cheng: Tsinghua University
Jing Wang: Tsinghua University
Xiaolin Sun: Peking University People’s Hospital
Xiaohui Liu: Tsinghua University
Haiteng Deng: Tsinghua University
Jinliang Yang: Sichuan University
Zhanguo Li: Tsinghua-Peking Center for Life Sciences
Wanli Liu: Tsinghua University
Ligong Chen: Tsinghua University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

Date: 2024
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DOI: 10.1038/s41467-023-44540-0

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