Fumarate suppresses B-cell activation and function through direct inactivation of LYN

  • Nat Chem Biol. 2022 Sep;18(9):954-962. doi: 10.1038/s41589-022-01052-0.
Jie Cheng   #  1  2 ,  Ying Liu   #  3 ,  Jinxin Yan   #  1  2 ,  Lina Zhao  1  2 ,  Yinglin Zhou  3 ,  Xuyang Shen  3 ,  Yunan Chen  3 ,  Yining Chen  1  2 ,  Xianbin Meng  4 ,  Xinxiang Zhang  5 ,  Peng Jiang  6  7
Affiliations
  • 1. School of Life Sciences, Tsinghua University, Beijing, China.
  • 2. Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 3. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
  • 4. National Center for Protein Science, Tsinghua University, Beijing, China.
  • 5. Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [email protected].
  • 6. School of Life Sciences, Tsinghua University, Beijing, China. [email protected].
  • 7. Tsinghua-Peking Center for Life Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 35710616 DOI: 10.1038/s41589-022-01052-0
Abstract

Activated B cells increase central carbon metabolism to fulfill their bioenergetic demands, yet the mechanistic basis for this, as well as metabolic regulation in B cells, remains largely unknown. Here, we demonstrate that B-cell activation reprograms the tricarboxylic acid cycle and boosts the expression of fumarate hydratase (FH), leading to decreased cellular fumarate abundance. Fumarate accumulation by FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation, proliferation and antibody production. Mechanistically, fumarate is a covalent inhibitor of tyrosine kinase Lyn, a key component of the BCR signaling pathway. Fumarate can directly succinate Lyn at C381 and abrogate Lyn activity, resulting in a block to B-cell activation and function in vitro and in vivo. Therefore, our findings uncover a previously unappreciated metabolic regulation of B cells, and reveal Lyn is a natural sensor of fumarate, connecting cellular metabolism to B-cell antigen receptor signaling.

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