| The peroxisome proliferator-activated receptory (PPARgamma) plays an essential role in fat cell development and is the molecular target of insulin-sensitizing drugs. Compiling evidence suggests that a major function of its insulin-sensitizing activity of this nuclear receptor is through antagonism of inflammatory pathways that ultimately result in loss of insulin action. I set out to test the hypothesis that this inflammatory repression required the modulation of co-repressor/histone deacetylase complexes on inflammatory promoters in murine macrophages. Here, I show that PPARgamma acts to repress transcriptional activation of inflammatory response genes by a mechanism requiring SUMOylation by PIAS1. SUMOylation targets PPARgamma to NCoR/HDAC3 corepressor complexes on inflammatory gene promoters, preventing recruitment of the ubiquitylation/19S proteosome machinery that mediates their signal-dependent clearance. These observations reveal a molecular mechanism that converts an agonist-bound nuclear receptor to a repressor of genes that control immune responses. Inhibition of the analogous SUMOylation system in Drosophila cells abolishes the ability of the orphan nuclear receptors Tailless and Eagle to repress inflammatory gene expression, indicating that core features of this transrepression pathway extend to other nuclear receptors and are, therefore, evolutionarily conserved. These findings provide the rationale for alternate approaches towards the treatment of inflammatory diseases including insulin resistance and atherosclerosis. |
