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.

journal_name

Circ Res

journal_title

Circulation research

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

doi

10.1161/CIRCRESAHA.111.258814

subject

Has Abstract

pub_date

2012-04-13 00:00:00

pages

e50-63

issue

8

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.111.258814

journal_volume

110

pub_type

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