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

• Authors: William Hudson, Emory University; Ian Michelle S. de Vera, Scripps Research Institute; Jerome C. Nwachukwu, Scripps Research Institute; Emily R. Weikum, Emory University; Austin G. Herbst, Emory University; Qin Yang, University of Colorado; David L. Bain, University of Colorado; Kendall W. Nettles, Scripps Research Institute; Douglas J. Kojetin, Scripps Research Institute; Eric Ortlund, Emory University
• Journal Title: Nature Communications
• Volume: Volume 9, Number 1
• Publisher: Nature Publishing Group: Nature Communications | 2018-04-06, Pages 1337-1337
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-018-03780-1
• Subjects: Chemistry, Pharmaceutical; Health Sciences, Pharmacology; Health Sciences, Immunology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; PROTEIN-PROTEIN-INTERACTION; DNA-BINDING; CRYSTAL-STRUCTURE; FUNCTIONAL ANTAGONISM; NEGATIVE REGULATION; GENE REPRESSION; LIGAND-BINDING; T-CELLS; C-JUN; TRANSCRIPTION

Abstract

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.