Nature 562, 600–604 (2018)

Credit: Nature

NF-E2-related factor 2 (NRF2) is a key regulator of oxidative stress and is normally sequestered in the cytoplasm by the Kelch-like ECH associated protein 1 (KEAP1). Covalent modification of reactive cysteines on KEAP1 by electrophiles alters the NRF2–KEAP1 interaction, resulting in NRF2 accumulation and pathway activation. Although covalent small-molecule inhibitors of KEAP1 have been described, Bollong et al. sought find an alternative means of activating NRF2, identifying the nonelectrophilic small molecule CBR-470-1 from a high-throughput screen. Target identification studies revealed that CBR-470-1 directly inhibits the glycolytic enzyme phosphoglycerate kinase 1 (PGK1), resulting in accumulation of metabolites including methylglyoxal (MGO). Interestingly, CBR-470-1 treatment or PGK1 knockdown resulted in the appearance of a high-molecular-mass form of KEAP1 that was associated with NRF2 activation and dependent on MGO. Finally, direct interaction of KEAP1 with MGO resulted in a new post-translational modification: a methylimidazole cross-link between C151 and R135 of KEAP1. Overall, these findings reveal a unique interplay between glucose metabolism, KEAP1 function and the cellular antioxidant response.