Coronin2A mediates actin-dependent de-repression of inflammatory response genes

Toll-like receptors (TLRs) function as initiators of inflammation through their ability to sense pathogen-associated molecular patterns and products of tissue damage(1,2). Transcriptional activation of many TLR-responsive genes requires an initial de-repression step in which NCoR co-repressor complexes are actively removed from target gene promoters to relieve basal repression(3,4). Ligand-dependent SUMOylation of liver X receptors (LXRs) potently suppresses TLR4-induced transcription by preventing the NCoR clearance step(5–7), but the underlying mechanisms remain enigmatic. Here, we provide evidence that Coronin 2A (Coro2A), a component of the NCoR complex of previously unknown function(8,9), mediates TLR-induced NCoR turnover by a mechanism involving interaction with oligomeric nuclear actin. SUMOylated LXRs block NCoR turnover by binding to a conserved SUMO2/3 interaction motif in Coro2A and preventing actin recruitment. Intriguingly, the LXR transrepression pathway can itself be inactivated by inflammatory signals that induce CaMKIIγ-dependent phosphorylation of LXR, leading to its deSUMOylation by the SUMO protease SENP3 and release from Coro2A. These findings reveal a Coro2A/actin-dependent mechanism for de-repression of inflammatory response genes that can be differentially regulated by phosphorylation and nuclear receptor signaling pathways that control immunity and homeostasis.