Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3,4,5 and transcription6. An important ‘sensor’ protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1–NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases.
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RNA-seq primary data are deposited in the Gene Expression Omnibus (GEO) under accession number GSE116642. Source data for all mouse experiments have been provided. Full scans for western blots and gels are available in the Supplementary Information. All other data are available on reasonable request.
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We thank S. Zhu for discussions about target identification experiments. Animal experiments were approved by the Scripps Research Institute Institutional Review Board. We are grateful for financial support of this work from the following: Kwanjeong Educational Fellowship (to G.L.); NIH MSTP Training Grant (T32GM007281 to J.S.C.); NIH R00CA175399, R01CA211916 and DP2GM128199 (R.E.M.); V Foundation for Cancer Research (V2015-020 to R.E.M.); Damon Runyon Cancer Research Foundation (DFS08-14); The Skaggs Institute for Chemical Biology, and The University of Chicago.
Nature thanks H. Christofk, A. Dinkova-Kostova, H. Lin and the anonymous reviewer(s) for their contribution to the peer review of this work.