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- Title
Coronin 2A mediates actin-dependent de-repression of inflammatory response genes.
- Authors
Huang, Wendy; Ghisletti, Serena; Saijo, Kaoru; Gandhi, Meghal; Aouadi, Myriam; Tesz, Greg J.; Zhang, Dawn X.; Yao, Joyee; Czech, Michael P.; Goode, Bruce L.; Rosenfeld, Michael G.; Glass, Christopher K.
- Abstract
Toll-like receptors (TLRs) function as initiators of inflammation through their ability to sense pathogen-associated molecular patterns and products of tissue damage. Transcriptional activation of many TLR-responsive genes requires an initial de-repression step in which nuclear receptor co-repressor (NCoR) complexes are actively removed from the promoters of target genes to relieve basal repression. Ligand-dependent SUMOylation of liver X receptors (LXRs) has been found to suppress TLR4-induced transcription potently by preventing the NCoR clearance step, but the underlying mechanisms remain enigmatic. Here we provide evidence that coronin 2A (CORO2A), a component of the NCoR complex of previously unknown function, mediates TLR-induced NCoR turnover by a mechanism involving interaction with oligomeric nuclear actin. SUMOylated LXRs block NCoR turnover by binding to a conserved SUMO2/SUMO3-interaction motif in CORO2A and preventing actin recruitment. Intriguingly, the LXR transrepression pathway can itself be inactivated by inflammatory signals that induce calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)-dependent phosphorylation of LXRs, leading to their deSUMOylation by the SUMO protease SENP3 and release from CORO2A. These findings uncover a CORO2A-actin-dependent mechanism for the de-repression of inflammatory response genes that can be differentially regulated by phosphorylation and by nuclear receptor signalling pathways that control immunity and homeostasis.
- Subjects
MICROFILAMENT proteins; ACTIN; GENE expression; NUCLEAR receptors (Biochemistry); OLIGOMERS; PHOSPHORYLATION; HOMEOSTASIS
- Publication
Nature, 2011, Vol 470, Issue 7334, p414
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature09703