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

KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, seve...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-05, Vol.120 (20), p.e2300763120-e2300763120
Main Authors: Ko, Yeonjin, Hong, Mannkyu, Lee, Seungbeom, Kumar, Manoj, Ibrahim, Lara, Nutsch, Kayla, Stanton, Caroline, Sondermann, Phillip, Sandoval, Braddock, Bulos, Maya L, Iaconelli, Jonathan, Chatterjee, Arnab K, Wiseman, R Luke, Schultz, Peter G, Bollong, Michael J
Format: Article
Language:English
Subjects:
Biological Sciences
Cysteine
Cysteine - metabolism
Glyceraldehyde
Glyceraldehyde 3-phosphate
Glycolysis
High-throughput screening
Kelch-Like ECH-Associated Protein 1 - chemistry
Metabolites
NF-E2-Related Factor 2 - metabolism
Oxidative metabolism
Oxidative Stress
Pyruvate kinase
Pyruvic acid
Reagents
Residues
Signal Transduction
Xenobiotics
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Summary:KEAP1 (Kelch-like ECH-associated protein), a cytoplasmic repressor of the oxidative stress responsive transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), senses the presence of electrophilic agents by modification of its sensor cysteine residues. In addition to xenobiotics, several reactive metabolites have been shown to covalently modify key cysteines on KEAP1, although the full repertoire of these molecules and their respective modifications remain undefined. Here, we report the discovery of sAKZ692, a small molecule identified by high-throughput screening that stimulates NRF2 transcriptional activity in cells by inhibiting the glycolytic enzyme pyruvate kinase. sAKZ692 treatment promotes the buildup of glyceraldehyde 3-phosphate, a metabolite which leads to S-lactate modification of cysteine sensor residues of KEAP1, resulting in NRF2-dependent transcription. This work identifies a posttranslational modification of cysteine derived from a reactive central carbon metabolite and helps further define the complex relationship between metabolism and the oxidative stress-sensing machinery of the cell.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2300763120