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. Epub 2022 Jun 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fumarate Hydratase / metabolism
  • Fumarates* / pharmacology
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, B-Cell* / metabolism
  • Signal Transduction
  • src-Family Kinases / metabolism

Substances

  • Fumarates
  • Receptors, Antigen, B-Cell
  • Protein-Tyrosine Kinases
  • src-Family Kinases
  • Fumarate Hydratase