A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ

Gabriel Pascual, Amy L. Fong, Sumito Ogawa, Amir Gamliel, Andrew C. Li, Valentina Perissi, David W. Rose, Timothy M. Willson, Michael G. Rosenfeld and Christopher K. Glass ()
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Gabriel Pascual: University of California San Diego
Amy L. Fong: University of California San Diego
Sumito Ogawa: University of California San Diego
Amir Gamliel: University of California San Diego
Andrew C. Li: University of California San Diego
Valentina Perissi: University of California San Diego
David W. Rose: University of California San Diego
Timothy M. Willson: GlaxoSmithKline
Michael G. Rosenfeld: University of California San Diego
Christopher K. Glass: University of California San Diego

Nature, 2005, vol. 437, issue 7059, 759-763

Abstract: Abstract Peroxisome proliferator-activated receptor-γ (PPAR-γ) has essential roles in adipogenesis and glucose homeostasis, and is a molecular target of insulin-sensitizing drugs1,2,3. Although the ability of PPAR-γ agonists to antagonize inflammatory responses by transrepression of nuclear factor kappa B (NF-κB) 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-γ represses the transcriptional activation of inflammatory response genes in mouse macrophages. The initial step of this pathway involves ligand-dependent SUMOylation of the PPAR-γ ligand-binding domain, which targets PPAR-γ 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-κB target genes that regulate immunity and homeostasis.

Date: 2005
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DOI: 10.1038/nature03988

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