Interferon-inducible factor 16 is a novel modulator of glucocorticoid action

A. Berry, L. Matthews, M. Jangani, J. Plumb, S. Farrow, N. Buchan, P. A. Wilson, D. Singh, D. W. Ray, R. P. Donn

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    Abstract

    Previously, we used cDNA expression profiling to identify genes associated with glucocorticoid (Gc) sensitivity. We now identify which of these directly influence Gc action. Interferon-inducible protein 16 (IFI16), bone morphogenetic protein receptor type II (BMPRII), and regulator of G-protein signaling 14 (RGS14) increased Gc transactivation, whereas sialyltransferase 4B (SIAT4B) had a negative effect. Amyloid β (A4) precursor-protein binding, family B, member 1 (APBB1/ Fe65) and neural cell expressed developmentally down-regulated 9 (NEDD9) were without effect. Only IFI16 potentiated Gc repression of NF-κB. In addition, IFI16 affected basal expression, and Gc induction of endogenous target genes. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand-dependent repression of GR expression, or the ligand-dependent induction of GR phosphorylation on Ser-211 or Ser-203. Coimmuno-precipitation revealed an interaction, suggesting that IFI16 modulation of GR function is mediated by protein crosstalk. Transfection analysis with GR mutants showed that the ligand-binding domain of GR binds IFI16 and is the target domain for IFI16 regulation. Analysis of human lung sections identified colocalization of GR and IFI16, suggesting a physiologically relevant interaction. We demonstrate that IFI16 is a novel modulator of GR function and show the importance of analyzing variation in Gc sensitivity in humans, using appropriate technology, to drive discovery. © The Author(s).
    Original languageEnglish
    Pages (from-to)1700-1713
    Number of pages13
    JournalFaseb Journal
    Volume24
    Issue number6
    DOIs
    Publication statusPublished - Jun 2010

    Keywords

    • IFI16
    • Inflammation
    • Nuclear receptor
    • Steroid sensitivity

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