title: Coronin 2A mediates actin-dependent de-repression of inflammatory response genes.
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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Huang
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.forename: Kaoru
authors.initials: K
authors.lastname: Saijo
authors.forename: Meghal
authors.initials: M
authors.lastname: Gandhi
authors.forename: Myriam
authors.initials: M
authors.lastname: Aouadi
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Tesz
authors.forename: Dawn X
authors.initials: DX
authors.lastname: Zhang
authors.forename: Joyee
authors.initials: J
authors.lastname: Yao
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Goode
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D058207:Sumoylation; D013864:Thioglycolates / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000199:Actins; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D008840:Microfilament Proteins; D057093:Orphan Nuclear Receptors; D013864:Thioglycolates; D051193:Toll-Like Receptors; C072061:coronin proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; C492190:Senp3 protein, mouse