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

Huang W, et al. Nature 470, 414-418(2011)

Speaker: Wei-Min Hung (洪偉珉)                                 Time: 15:00 ~ 16:00, Feb. 22, 2012

Commentator: Dr. Hsiao-Sheng Liu (劉校生 老師)     Place: Room 601

Abstract

Under basal conditions, the toll-like receptor (TLR)-responsive promoters are occupied by the nuclear receptor co-repressor (NCoR) complexes. After stimulation, NCoR complexes are actively removed from the promoters of target genes to relieve repression¹. The induction of an inflammatory response is essential for host defense during infection, but it is also important to limit the harmful effects of inflammation when it is inappropriately sustained or increased. Previous studies have shown that SUMOylated liver X receptors (LXRs) suppress TLR4-induced transcription by preventing the NCoR clearance², but the underlying mechanisms remain unclear. In this study, the authors found that SUMOylated LXRs blocked NCoR turnover by binding to a SUMO-interaction motif in coronin 2A and preventing nuclear actin recruitment. SUMOylated LXR entered the trans-repression pathway by docking to the NCoR complex at the promoters of LPS/TLR4 response genes, thereby preventing actin-dependent de-repression and activation of inflammatory response genes. TLR2 activation induced calcium/calmodulin-dependent protein kinase II(CaMKII) that abolished LXRs trans-repression of TLR4 signaling³. CaMKII-dependent phosphorylation of LXRs produces a docking site for SUMO protease SENP3, thereby inactivating its trans-repression activity. Thioglycollate-induced sterile peritonitis model in mice also confirmed the coronin2A/NCoR clearance pathway in vivo. Collectively, coronin 2A/actin-dependent mechanism for the de-repression of inflammatory response genes can be differentially regulated by phosphorylation and by nuclear receptor signaling pathways that control innate immune response.

References

1. Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nature Rev. Immunol. 9, 692–703 (2009).

2. Ghisletti, S. et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ. Mol. Cell 25, 57–70 (2007).

3. Huang, W. et al. Transcriptional integration of TLR2 and TLR4 signaling at the NCoR derepression checkpoint. Mol. Cell 35, 48–57 (2009).