JOURNAL CLUB

S-lactoyl modification of KEAP1 by a reactive glycolytic metabolite activates NRF2 signaling-PNAS

Several reactive endogenous metabolites have been shown to activate the NRF2-driven oxidative stress response in mammalian cells. Here, we expand this repertoire of reactive metabolites by showing that pharmacological inhibition of pyruvate kinase, the last step in glycolysis, results in the accumulation of glyceraldehyde 3-phosphate, a metabolite that results in the covalent modification and inactivation of the NRF2 repressor protein KEAP1. This work identifies a nonenzymatically derived posttranslational modification of cysteine, termed S-lactoylation, and further builds upon existing data that glycolysis directly communicates to the KEAP1–NRF2 signaling pathway through reactive metabolite-derived modifications of cysteine.