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The interferon stimulated gene 12 inactivates vasculoprotective functions of NR4A nuclear receptors.
RATIONALEInnate 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.
OBJECTIVEThe 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 RESULTSWe 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.
CONCLUSIONSThese 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.
Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Austria. firstname.lastname@example.org, , , , , , , , , , , ,
Circulation research 110:8 2012 Apr 13 pg e50-63
MeSHActive Transport, Cell Nucleus
Carotid Artery Injuries
Disease Models, Animal
Gene Expression Regulation
Mice, 129 Strain
Mice, Inbred C57BL
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Nuclear Receptor Subfamily 4, Group A, Member 1
Protein Interaction Domains and Motifs
Receptors, Cytoplasmic and Nuclear
Vascular System Injuries
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't