Journal Article

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

Zhao, Lina, Meng, Xianbin, Cheng, Jie, Shen, Xuyang, Chen, Yunan, Liu, Ying, Yan, Jinxin, Zhou, Yinglin, Jiang, Peng, Chen, Yining, Zhang, Xinxiang

2022

Overview

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.B-cell activation reprograms the TCA cycle and reduces cellular fumarate levels. Increased fumarate caused by fumarase inhibition or dimethyl-fumarate treatment directly succinates and inhibits LYN, leading to impaired B-cell activation and function.

• Publisher: Nature Publishing Group
• Subject: Activated carbon / Antibodies / Antigens / B-cell receptor / Cell activation / Enzyme inhibitors / Fumarase / Inactivation / Kinases / Lymphocytes B / Metabolism / Protein-tyrosine kinase / Signal transduction / Signaling / Tricarboxylic acid cycle / Tyrosine