Faculty Opinions recommendation of A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.

The peroxisome proliferator-activated receptor γ (PPARγ) plays essential roles in adipogenesis and glucose homeostasis and is a molecular target of insulin-sensitizing drugs 1-3 .Although the ability of PPARγ agonists to antagonize inflammatory responses by transrepression of nuclear factor kappaB (NF-κB) target genes is linked to anti-diabetic 4 and antiatherogenic actions 5 , the mechanisms remain poorly understood.Here we report the identification of a molecular pathway by which PPARγ represses transcriptional activation of inflammatory response genes in macrophages.The initial step of this pathway involves ligand-dependent sumoylation of the PPARγ ligand-binding domain, which targets PPARγ to nuclear receptor co-repressor (NCoR)/histone deacetylase-3 (HDAC3) complexes on inflammatory gene promoters.This in turn prevents recruitment of the ubiquitylation/19S proteosome machinery that normally mediates the signal-dependent removal of corepressor complexes required for gene activation.As a result, NCoR complexes are not cleared from the promoter and target genes are maintained in a repressed state.This mechanism provides an explanation for how an agonist-bound nuclear receptor can be converted from an activator of transcription to a promoter-specific repressor of NF-κB target genes that regulate immunity and homeostasis.NCoR, and the related factor, silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), are components of corepressor complexes containing HDAC3, transducin beta-like protein-1 (TBL1) and TBLR1 that interact with a subset of unliganded nuclear receptors, mediating active transcriptional repression 6-12 .Ligand-dependent dismissal of these complexes requires Ubc5-dependent ubiquitylation and proteosomal degradation, with Tblr1 functioning as an essential E3 ligase 13 .Recent studies indicate that NCoR/SMRT complexes are also required for basal repression of a subset of NF-κB and AP-1 target genes 13-15 , with loss of NCoR resulting in a partially activated phenotype in macrophages 14 .We noted that a number of inflammatory response genes that are de-repressed in NCoR-deficient macrophages are also subject to transrepression by PPARγ agonists, suggesting a possible role of NCoR in this process.