A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.
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.
Pascual
Gabriel
G
Department of Cellular and Molecular Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Fong
Amy L
AL
Ogawa
Sumito
S
Gamliel
Amir
A
Li
Andrew C
AC
Perissi
Valentina
V
Rose
David W
DW
Willson
Timothy M
TM
Rosenfeld
Michael G
MG
Glass
Christopher K
CK
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D007249:Inflammation / Q000235:genetics*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D008024:Ligands; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D016328:NF-kappa B; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D000099186:Histone Deacetylase 3; C539128:Ncor1 protein, mouse; C494211:Pias1 protein, mouse; C496317:Nos2 protein, mouse