2. Academic Validation
  3. MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation

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

  • Nat Commun. 2024 Jan 2;15(1):163. doi: 10.1038/s41467-023-44540-0.
Wenna Chi # 1 2,  Na Kang # 3 4,  Linlin Sheng # 1,  Sichen Liu # 3,  Lei Tao 1 2,  Xizhi Cao 1,  Ye Liu 1,  Can Zhu 3,  Yuming Zhang 1,  Bolong Wu 1,  Ruiqun Chen 1,  Lili Cheng 1,  Jing Wang 3,  Xiaolin Sun 5 6,  Xiaohui Liu 7,  Haiteng Deng 7,  Jinliang Yang 2,  Zhanguo Li 4 5 6,  Wanli Liu 8 9,  Ligong Chen 10 11
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, China.
  • 2 Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610065, China.
  • 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, 100084, China.
  • 4 Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 5 Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
  • 6 Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, 100044, China.
  • 7 National Center for Protein Science, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 8 State Key Laboratory of Membrane Biology, School of Life Sciences, Institute for Immunology, China Ministry of Education Key Laboratory of Protein Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, 100084, China. [email protected].
  • 9 Tsinghua-Peking Center for Life Sciences, Beijing, China. [email protected].
  • 10 School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084, China. [email protected].
  • 11 Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610065, China. [email protected].
  • # Contributed equally.
PMID: 38167945 DOI: 10.1038/s41467-023-44540-0
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.

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