1. Department of Cellular and Molecular Medicine,
2. Howard Hughes Medical Institute,
3. Department of Medicine, and
4. Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA
5. GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, North Carolina 27709, USA

Correspondence to: Christopher K. Glass^1,3 Correspondence and requests for materials should be addressed to C.K.G. (Email: cglass@ucsd.edu).

Abstract

Peroxisome proliferator-activated receptor- (PPAR-) has essential roles in adipogenesis and glucose homeostasis, and is a molecular target of insulin-sensitizing drugs^{1, 2, 3}. Although the ability of PPAR- agonists to antagonize inflammatory responses by transrepression of nuclear factor kappa B (NF-B) target genes is linked to antidiabetic⁴ and antiatherogenic actions⁵, the mechanisms remain poorly understood. Here we report the identification of a molecular pathway by which PPAR- represses the transcriptional activation of inflammatory response genes in mouse macrophages. The initial step of this pathway involves ligand-dependent SUMOylation of the PPAR- ligand-binding domain, which targets PPAR- 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-B target genes that regulate immunity and homeostasis.

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