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The interferon stimulated gene 12 inactivates vasculoprotective functions of NR4A nuclear receptors.

Abstract

RATIONALE
Innate and adaptive immune responses alter numerous homeostatic processes that are controlled by nuclear hormone receptors. NR4A1 is a nuclear receptor that is induced in vascular pathologies, where it mediates protection.
OBJECTIVE
The underlying mechanisms that regulate the activity of NR4A1 during vascular injury are not clear. We therefore searched for modulators of NR4A1 function that are present during vascular inflammation.
METHODS AND RESULTS
We report that the protein encoded by interferon stimulated gene 12 (ISG12), is a novel interaction partner of NR4A1 that inhibits the transcriptional activities of NR4A1 by mediating its Crm1-dependent nuclear export. Using 2 models of vascular injury, we show that ISG12-deficient mice are protected from neointima formation. This effect is dependent on the presence of NR4A1, as mice deficient for both ISG12 and NR4A1 exhibit neointima formation similar to wild-type mice.
CONCLUSIONS
These findings identify a previously unrecognized feedback loop activated by interferons that inhibits the vasculoprotective functions of NR4A nuclear receptors, providing a potential new therapeutic target for interferon-driven pathologies.

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  • Authors

    Papac-Milicevic N, Breuss JM, Zaujec J, Ryban L, Plyushch T, Wagner GA, Fenzl S, Dremsek P, Cabaravdic M, Steiner M, Glass CK, Binder CJ, Uhrin P, Binder BR

    Source

    Circulation research 110:8 2012 Apr 13 pg e50-63

    MeSH

    Active Transport, Cell Nucleus
    Animals
    Carotid Artery Injuries
    Cells, Cultured
    Disease Models, Animal
    Endothelial Cells
    Feedback, Physiological
    Femoral Artery
    Gene Expression Regulation
    Inflammation
    Interferons
    Karyopherins
    Membrane Proteins
    Mice
    Mice, 129 Strain
    Mice, Inbred C57BL
    Mice, Knockout
    Muscle, Smooth, Vascular
    Myocytes, Smooth Muscle
    Nuclear Receptor Subfamily 4, Group A, Member 1
    Protein Interaction Domains and Motifs
    Proteins
    RNA Interference
    Receptors, Cytoplasmic and Nuclear
    Time Factors
    Transcription, Genetic
    Transfection
    Vascular System Injuries

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22427340