Coronin 2A mediates actin-dependent de-repression of inflammatory response genes

Wendy Huang, Serena Ghisletti, Kaoru Saijo, Meghal Gandhi, Myriam Aouadi, Greg J. Tesz, Dawn X. Zhang, Joyee Yao, Michael P. Czech, Bruce L. Goode, Michael G. Rosenfeld, Christopher K. Glass

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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.

Original languageEnglish
Pages (from-to)414-418
Number of pages5
JournalNature
Volume470
Issue number7334
DOIs
Publication statusPublished - Feb 17 2011

ASJC Scopus subject areas

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    Huang, W., Ghisletti, S., Saijo, K., Gandhi, M., Aouadi, M., Tesz, G. J., Zhang, D. X., Yao, J., Czech, M. P., Goode, B. L., Rosenfeld, M. G., & Glass, C. K. (2011). Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature, 470(7334), 414-418. https://doi.org/10.1038/nature09703