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 damage1,2. 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 repression3,4. Ligand-dependent SUMOylation of liver X receptors (LXRs) potently suppresses TLR4-induced transcription by preventing the NCoR clearance step5–7, 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 SUMO2/3 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.