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

Circ Res. 2012 Apr 13;110(8):e50-63. doi: 10.1161/CIRCRESAHA.111.258814. Epub 2012 Mar 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • IFI27 protein, human
  • ISG12b1 protein, mouse
  • Karyopherins
  • Membrane Proteins
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • exportin 1 protein
  • Interferons