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

Nature. 2005 Sep 29;437(7059):759-63. doi: 10.1038/nature03988. Epub 2005 Aug 28.


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 types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Down-Regulation* / drug effects
  • Histone Deacetylases / metabolism
  • Inflammation / genetics*
  • Ligands
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Mice
  • Multiprotein Complexes / metabolism
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Co-Repressor 1
  • PPAR gamma / metabolism*
  • Protein Binding / drug effects
  • Protein Inhibitors of Activated STAT
  • Proteins / metabolism
  • Repressor Proteins / metabolism*
  • SUMO-1 Protein / metabolism*


  • Ligands
  • Lipopolysaccharides
  • Multiprotein Complexes
  • NF-kappa B
  • Ncor1 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • PPAR gamma
  • Pias1 protein, mouse
  • Protein Inhibitors of Activated STAT
  • Proteins
  • Repressor Proteins
  • SUMO-1 Protein
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Histone Deacetylases
  • histone deacetylase 3