A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation

The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPAR gamma coactivator 1 alpha (PGC1 alpha) and that signaling via receptor activator of nuclear factor kappa -B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1 beta complex that coactivates nuclear factor kappa -B (NF kappa B)- and activator protein 1 (AP - 1)- dependentgenes required for osteoclast differentiation. Here, we demonstrate that activation of Toll -like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1 beta coactivator complex. Receptor- specific utilization of TNF receptor- associated factor 6 (TRAF6) and downstream activation of extracellular signal- regulated kinase 1 (ERK1) and TANK- binding kinase 1 (TBK1) accounts for the common ability of RANK and TLR4 to drive assembly of an NCoR/HDAC3/PGC1 beta complex in macrophages. ERK1, the p65 component of NF kappa B, and the p300 histone acetyltransferase (HAT) are also components of the induced complex and are associated with local histone acetylation and transcriptional activation of TLR4- dependent enhancers and promoters. These observations identify a TLR4/TRAF6- dependent signaling pathway that converts NCoR from a corepressor of nuclear receptors to a coactivator of NF kappa B and AP -1 that may be relevant to functions of NCoR in other developmental and homeostatic processes.