The Glucocorticoid Receptor Inhibits NRF2-Mediated Expression of SLC7A11

SLC7A11 encodes the glutamate-cystine exchanger xCT, which is a key regulator of intracellular antioxidant capacity and extracellular glutamate levels. We have identified SLC7A11 as a direct target of the glucocorticoid receptor (GR). The GR agonist dexamethasone represses SLC7A11 expression in multiple cell types, from epithelial cells to astrocytes. Dexamethasone induces GR binding to multiple regulatory DNA regions at the SLC7A11 locus, including two prominent NRF2-targeted antioxidant response element (ARE) regions. Enhancer dissection and chromatin immunoprecipitation (ChIP) assays support a tethering model in which GR directly interacts with ARE-bound NRF2 at SLC7A11 and represses NRF2-mediated activation of this gene.