IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-03780-1.html
   My bibliography  Save this article

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

Author

Listed:
  • William H. Hudson

    (Emory University School of Medicine
    Winship Cancer Institute
    Emory University School of Medicine)

  • Ian Mitchelle S. de Vera

    (The Scripps Research Institute
    Saint Louis University School of Medicine)

  • Jerome C. Nwachukwu

    (The Scripps Research Institute)

  • Emily R. Weikum

    (Emory University School of Medicine
    Winship Cancer Institute)

  • Austin G. Herbst

    (Emory University School of Medicine)

  • Qin Yang

    (University of Colorado Anschutz Medical Campus, Aurora)

  • David L. Bain

    (University of Colorado Anschutz Medical Campus, Aurora)

  • Kendall W. Nettles

    (The Scripps Research Institute)

  • Douglas J. Kojetin

    (The Scripps Research Institute)

  • Eric A. Ortlund

    (Emory University School of Medicine
    Winship Cancer Institute)

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.

Suggested Citation

  • William H. Hudson & Ian Mitchelle S. de Vera & Jerome C. Nwachukwu & Emily R. Weikum & Austin G. Herbst & Qin Yang & David L. Bain & Kendall W. Nettles & Douglas J. Kojetin & Eric A. Ortlund, 2018. "Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03780-1
    DOI: 10.1038/s41467-018-03780-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-03780-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-018-03780-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Devesh Bhimsaria & José A. Rodríguez-Martínez & Jacqui L. Mendez-Johnson & Debostuti Ghoshdastidar & Ashwin Varadarajan & Manju Bansal & Danette L. Daniels & Parameswaran Ramanathan & Aseem Z. Ansari, 2023. "Hidden modes of DNA binding by human nuclear receptors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03780-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.