SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR.
The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of genes implicated in lipid homeostasis and inflammation. PPARalpha trans-activity is enhanced by recruitment of coactivators such as SRC1 and CBP/p300 and is inhibited by binding of corepressors such as NCoR and SMRT. In addition to ligand binding, PPARalpha activity is regulated by post-translational modifications such as phosphorylation and ubiquitination. In this report, we demonstrate that hPPARalpha is SUMOylated by SUMO-1 on lysine 185 in the hinge region. The E2-conjugating enzyme Ubc9 and the SUMO E3- ligase PIASy are implicated in this process. In addition, ligand treatment decreases the SUMOylation rate of hPPARalpha. Finally, our results demonstrate that SUMO-1 modification of hPPARalpha down-regulates its trans-activity through the specific recruitment of corepressor NCoR but not SMRT leading to the differential expression of a subset of PPARalpha target genes. In conclusion, hPPARalpha SUMOylation on lysine 185 down-regulates its trans-activity through the selective recruitment of NCoR.
Pourcet
Benoit
B
Université Lille Nord de France.
Pineda-Torra
Inés
I
Derudas
Bruno
B
Staels
Bart
B
Glineur
Corine
C
D001665:Binding Sites; D002460:Cell Line; D056970:Co-Repressor Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism* / Q000502:physiology; D021381:Protein Transport; D025842:SUMO-1 Protein / Q000378:metabolism*
D056970:Co-Repressor Proteins; C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1; D047493:PPAR alpha; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D008239:Lysine