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

Nature volume 470, pages 414–418 (2011)Cite this article

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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 damage1,2. 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 repression3,4. Ligand-dependent SUMOylation of liver X receptors (LXRs) has been found to suppress TLR4-induced transcription potently by preventing the NCoR clearance step5,6,7, but the underlying mechanisms remain enigmatic. Here we provide evidence that coronin 2A (CORO2A), a component of the NCoR complex of previously unknown function8,9, 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.

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Figure 1: The SIM of CORO2A is required for recruiting SUMOylated LXR to NCoR-occupied pro-inflammatory gene promoters.
Figure 2: The actin-binding domain of CORO2A is required for LPS de-repression of inflammatory gene promoters.
Figure 3: The LXR–CORO2A axis is disrupted by CaMKIIγ phosphorylation and SENP3 deSUMOylation of LXR.
Figure 4: Function of the CORO2A–LXR–CaMKII pathway in thioglycollate-elicited peritonitis.

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Acknowledgements

We thank S. Amano for preparation of GeRP delivery spheres. We thank L. Bautista for assistance with preparation of the manuscript. W.H. was supported by NRSA 1F31DK083913. These studies were supported by National Institutes of Health grants CA52599, DK074868, HC088093 and DK085853 and a Leducq Foundation Transatlantic Network Grant. M.G.R. is an investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Serena Ghisletti

    Present address: Present address: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.,

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Wendy Huang, Serena Ghisletti, Kaoru Saijo, Dawn X. Zhang, Joyee Yao & Christopher K. Glass

  2. Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA ,

    Wendy Huang & Dawn X. Zhang

  3. Department of Biology, Rosenstiel Basic Medical Science Research Center, Brandeis University, Waltham, 02454, Massachusetts, USA

    Meghal Gandhi & Bruce L. Goode

  4. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, USA ,

    Myriam Aouadi, Greg J. Tesz & Michael P. Czech

  5. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA,

    Michael G. Rosenfeld & Christopher K. Glass

  6. Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA ,

    Michael G. Rosenfeld

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Contributions

W.H., S.G., K.S., M.C., B.L.G., M.G.R. and C.K.G. conceived the project and planned experiments and analysis, which were performed by W.H., S.G., K.S., M.G., M.A., G.T., D.Z. and J.Y. The entire project was supervised by C.K.G., who wrote the manuscript with W.H.

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Correspondence to Christopher K. Glass.

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Competing interests

M.P.C. is a consultant to, and an equity holder in, RXi Pharmaceuticals, which has licensed the GeRP siRNA delivery method.

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Huang, W., Ghisletti, S., Saijo, K. et al. Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature 470, 414–418 (2011). https://doi.org/10.1038/nature09703

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