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Author Notes:

Eric A. Ortlund, Email: eortlun@emory.edu.

Conceived and designed experiments: W.H.H., I.M.S.d.V., J.C.N., K.W.N., D.J.K., and E.A.O.

Performed the experiments: W.H.H., I.M.S.d.V., E.R.W., A.G.H,. J.C.N., K.W.N., D.J.K., and E.A.O.

Contributed new reagents/tools: Q.Y. and D.L.B.

Contributed to writing the manuscript: W.H.H., I.M.S.d.V., E.R.W., J.C.N., K.W.N., D.J.K., and E.A.O.

We thank Oskar Laur of the Emory Cloning Core for assistance with generating reporter constructs and Luis Franco (NIH/NIAID) for assistance conducting RNA-seq experiments.

The authors declare no competing interests.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Subjects:

Research Funding:

W.H.H. is supported by an American Heart Association (AHA) predoctoral fellowship (13PRE16920012) and by a U.S. National Institutes of Health (NIH) training grant to Emory University (5T32GM008602).

E.R.W. was supported by a National Institute of Health predoctoral NRSA (1F31GM113397-01A1).

A.G.H was supported by a Howard Hughes Medical Institute Science Education Program award (#52006923) to Emory University.

E.A.O. is supported by NIH grant R01DK095750 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), by an AHA grant 14GRNT20460124, and a W. M. Keck Foundation Medical Research Grant.

D.J.K. is supported by NIH grant R01DK101871 from the NIDDK and GM114420 from GM.

J.C.N. is supported by the BallenIsles Men’s Golf Association.

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

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

Tools:

Journal Title:

Nature Communications

Volume:

Volume 9, Number 1

Publisher:

, Pages 1337-1337

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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