Transcriptional Integration of TLR2 and TLR4 Signaling at the NCoR Derepression Checkpoint

Activation of toll-like receptors (TLRs) leads to derepression and subsequent activation of inflammatory response genes that play essential roles in innate and acquired immunity. Derepression requires signal-dependent turnover of the nuclear receptor corepressor NCoR from target promoters, but the mechanisms remain poorly understood. Here, we report that TLR4 uses NF kappa B to deliver IKK epsilon to target promoters that contain integrated circuits of kappa B and AP-1 sites, resulting in local phosphorylation of c-Jun and subsequent NCoR clearance. In contrast, TLR2 signaling 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 kappa B elements. Intriguingly, the IKK epsilon-dependent clearance pathway is sensitive to transrepression by liver X receptors, while the CaMKII-dependent pathway is not. These findings reveal mechanisms for integration of TLR, calcium, and nuclear receptor signaling pathways that underlie pathogen-specific responses and disease-specific programs of inflammation.