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- Title
A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.
- Authors
Pascual, Gabriel; Fong, Amy L; Ogawa, Sumito; Gamliel, Amir; Li, Andrew C; Perissi, Valentina; Rose, David W; Willson, Timothy M; Rosenfeld, Michael G; Glass, Christopher K
- Abstract
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has essential roles in adipogenesis and glucose homeostasis, and is a molecular target of insulin-sensitizing drugs. Although the ability of PPAR-gamma agonists to antagonize inflammatory responses by transrepression of nuclear factor kappa B (NF-kappaB) target genes is linked to antidiabetic and antiatherogenic actions, the mechanisms remain poorly understood. Here we report the identification of a molecular pathway by which PPAR-gamma represses the transcriptional activation of inflammatory response genes in mouse macrophages. The initial step of this pathway involves ligand-dependent SUMOylation of the PPAR-gamma ligand-binding domain, which targets PPAR-gamma to nuclear receptor corepressor (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-kappaB target genes that regulate immunity and homeostasis.
- Publication
Nature, 2005, Vol 437, Issue 7059, p759
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature03988