Transcriptional activity of peroxisome proliferator-activated receptor γ is modulated by SUMO-1 modification

Abstract

Covalent modification of many transcription factors with SUMO-1 is emerging as a key role of trans-activational regulation. Here, we demonstrate that peroxisome proliferator-activated receptor (PPAR) γ, which is a ligand-activated nuclear receptor, is modified by SUMO-1. Sumoylation of PPARγ mainly occurs at a lysine residue within the activation function 1 domain. Furthermore, we show that the PIAS family proteins, PIAS1 and PIASxβ, function as E3 ligases (ubiquitin-protein isopeptide ligase) for PPARγ. PPARγ interacts directly with PIASxβ in a ligand-independent manner. Analysis using a PPARγ mutant with a disrupted sumoylation site shows that modification of PPARγ by SUMO-1 represses its transcriptional activity. Interestingly, PIASxβ and Ubc9 enhance the transcriptional activity of PPARγ independent of PPARγ sumoylation. Furthermore, PPARγ ligand-induced apoptosis in a human hepatoblastoma cell line, HepG2, is significantly enhanced by ectopic production of the sumoylation-mutant PPARγ. These results suggest that the PPARγ-dependent transactivation pathway seems to be modulated by SUMO-1 modification and may serve as a novel target for apoptosis-induction therapy in cancer cells.