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Regulating inflammation : nuclear receptor and nuclear actin crosstalk at the nuclear receptor co-repressor and coronin 2A checkpoint


Toll-like receptors (TLRs) play important roles as initiators of inflammation through their ability to sense pathogen-associated molecular patterns and products of tissue damage. Activation of TLRs leads to de-repression and subsequent activation of inflammatory response genes that play essential roles in innate and acquired immunity. Derepression of TLR responsive genes involves active removal of the NCoR co-repressor complexes from target gene promoters to relieve basal repression, but the mechanisms remain poorly understood. Here, we report that TLR4 utilizes NFkB to deliver IKKe ; to target promoters that contain ìntegrated circuits' of kB and AP-1 sites, resulting in local phosphorylation of c-Jun and subsequent NCoR clearance. Ligand-dependent SUMOylation of liver X receptors (LXRs) potently suppresses TLR4-induced transcription 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 and SUMOylated LXRs block NCoR turnover by binding to a conserved SUMO2/3 interaction motif in Coro2A and preventing actin recruitment. Different from TLR4 signalling, TLR2 ligand leads to rapid activation of CaMKII and phosphorylation of the TBLR1 component of NCoR complexes, bypassing the requirement for c-Jun-phosphorylation and enabling NCoR clearance from promoters lacking integrated kB elements. Intriguingly, while the TLR4-IKKe-dependent clearance pathway is sensitive to transrepression by Liver X Receptors, the TLR2-CaMKII-dependent pathway is not. We found that CaMKIIg-dependent phosphorylation of LXR leads to its deSUMOylation by the SUMO protease SENP3 and release from Coro2A. Together, these findings reveal a Coro2A/actin-dependent mechanism for de-repression of inflammatory response genes that can be differentially regulated by kinase-phosphorylation and nuclear receptor signaling pathways that underlie pathogen-specific responses and disease-specific programs of inflammation

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