Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements

Glucocorticoids (GCs) are potent repressors of NF-κB activity, making them a preferred choice for treatment of inflammation-driven conditions. Despite the widespread use of GCs in the clinic, current models are inadequate to explain the role of the glucocorticoid receptor (GR) within this critical signaling pathway. GR binding directly to NF-κB itself—tethering in a DNA binding-independent manner—represents the standing model of how GCs inhibit NF-κB-driven transcription. We demonstrate that direct binding of GR to genomic NF-κB response elements (κBREs) mediates GR-driven repression of inflammatory gene expression. We report five crystal structures and solution NMR data of GR DBD-κBRE complexes, which reveal that GR recognizes a cryptic response element between the binding footprints of NF-κB subunits within κBREs. These cryptic sequences exhibit high sequence and functional conservation, suggesting that GR binding to κBREs is an evolutionarily conserved mechanism of controlling the inflammatory response. Glucocorticoid receptor (GR) regulates immunity and inflammation but the mechanisms by which GR represses proinflammatory genes are still being debated. Here the authors use a multidisciplinary approach and show that GR binds to a cryptic site within genome-wide NFκB DNA response elements to repress pro-inflammatory genes.