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

Nature. 2011 Feb 17;470(7334):414-8. doi: 10.1038/nature09703.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / chemistry
  • Actins / metabolism*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Line
  • Cysteine Endopeptidases
  • Gene Expression Regulation* / drug effects
  • Gene Knockdown Techniques
  • HeLa Cells
  • Homeostasis / genetics
  • Humans
  • Inflammation / genetics*
  • Lipopolysaccharides / pharmacology
  • Liver X Receptors
  • Mice
  • Microfilament Proteins / chemistry
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Orphan Nuclear Receptors / metabolism
  • Peptide Hydrolases / metabolism
  • Peritonitis / chemically induced
  • Peritonitis / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Protein Structure, Tertiary
  • Signal Transduction
  • Sumoylation
  • Thioglycolates / pharmacology
  • Toll-Like Receptors / metabolism


  • Actins
  • Lipopolysaccharides
  • Liver X Receptors
  • Microfilament Proteins
  • Orphan Nuclear Receptors
  • Thioglycolates
  • Toll-Like Receptors
  • coronin proteins
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Peptide Hydrolases
  • Cysteine Endopeptidases
  • Senp3 protein, mouse