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

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.

Authors:
 [1];  [2]; ORCiD logo [3];  [1];  [4];  [5];  [5];  [3]; ORCiD logo [3];  [1]
  1. Emory Univ. School of Medicine, Atlanta, GA (United States); Winship Cancer Inst., Atlanta, GA (United States)
  2. Saint Louis Univ. School of Medicine, MO (United States); The Scripps Research Inst., Jupiter, FL (United States)
  3. The Scripps Research Inst., Jupiter, FL (United States)
  4. Emory Univ. School of Medicine, Atlanta, GA (United States)
  5. Univ. of Colorado Anschutz Medical Campus, Aurora, CO (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); NIH/NIAID; National Inst. of Diabetes and Digestive and Kidney Diseases (NIDDK)
OSTI Identifier:
1434754
Grant/Contract Number:  
5T32GM008602; R01DK095750; 14GRNT20460124; R01DK101871
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; NMR spectroscopy; Transcriptional regulatory elements; X-ray crystallography

Citation Formats

Hudson, William H., de Vera, Ian Mitchelle S., Nwachukwu, Jerome C., Weikum, Emily R., Herbst, Austin G., Yang, Qin, Bain, David L., Nettles, Kendall W., Kojetin, Douglas J., and Ortlund, Eric A. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. United States: N. p., 2018. Web. doi:10.1038/s41467-018-03780-1.
Hudson, William H., de Vera, Ian Mitchelle S., Nwachukwu, Jerome C., Weikum, Emily R., Herbst, Austin G., Yang, Qin, Bain, David L., Nettles, Kendall W., Kojetin, Douglas J., & Ortlund, Eric A. Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements. United States. doi:10.1038/s41467-018-03780-1.
Hudson, William H., de Vera, Ian Mitchelle S., Nwachukwu, Jerome C., Weikum, Emily R., Herbst, Austin G., Yang, Qin, Bain, David L., Nettles, Kendall W., Kojetin, Douglas J., and Ortlund, Eric A. Fri . "Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements". United States. doi:10.1038/s41467-018-03780-1. https://www.osti.gov/servlets/purl/1434754.
@article{osti_1434754,
title = {Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements},
author = {Hudson, William H. and de Vera, Ian Mitchelle S. and Nwachukwu, Jerome C. and Weikum, Emily R. and Herbst, Austin G. and Yang, Qin and Bain, David L. and Nettles, Kendall W. and Kojetin, Douglas J. and Ortlund, Eric A.},
abstractNote = {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.},
doi = {10.1038/s41467-018-03780-1},
journal = {Nature Communications},
issn = {2041-1723},
number = 1,
volume = 9,
place = {United States},
year = {2018},
month = {4}
}

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