Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses

Immunometabolism is critical in the regulation of immunity and inflammation; however, the mechanism of preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) in the glycolysis branching pathway is specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S-D-lactoylglutathione (SLG) accumulates in the cytosol and directly induces D-lactyllysine modification of proteins. This nonenzymatic lactylation by SLG is greatly facilitated by a nearby cysteine residue, as it initially reacts with SLG to form a reversible S-lactylated thiol intermediate, followed…

• NN
  National Natural Science Foundation of China

  Awards: 31722019, 82070765, 81971499, 82388201
• SM
  Second Military Medical University
• SS
  Shanghai Shuguang Program
• NS
  Natural Science Foundation of Zhejiang Province

  Award: LZ20H290001