title: The interferon stimulated gene 12 inactivates vasculoprotective functions of NR4A nuclear receptors.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Austria. nikolina.papac@meduniwien.ac.at
authors.forename: Nikolina
authors.initials: N
authors.lastname: Papac-Milicevic
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Breuss
authors.forename: Jan
authors.initials: J
authors.lastname: Zaujec
authors.forename: Lubos
authors.initials: L
authors.lastname: Ryban
authors.forename: Tatiana
authors.initials: T
authors.lastname: Plyushch
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Wagner
authors.forename: Sabine
authors.initials: S
authors.lastname: Fenzl
authors.forename: Paul
authors.initials: P
authors.lastname: Dremsek
authors.forename: Muris
authors.initials: M
authors.lastname: Cabaravdic
authors.forename: Marianne
authors.initials: M
authors.lastname: Steiner
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Pavel
authors.initials: P
authors.lastname: Uhrin
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D020212:Carotid Artery Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007372:Interferons / Q000378:metabolism; D028884:Karyopherins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D057772:Vascular System Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000097606:Exportin 1 Protein
chemical_list: D007372:Interferons; D028884:Karyopherins; D008565:Membrane Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C406887:IFI27 protein, human; C539232:ISG12b1 protein, mouse; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse