Université Lille Nord de France.
J Biol Chem. 2010 Feb 26;285(9):5983-92. doi: 10.1074/jbc.M109.078311. Epub 2009 Dec 2.
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.
核受体过氧化物酶体增殖物激活受体α（PPARα）是参与脂质稳态和炎症的基因的关键调节剂。PPARα 的转录活性通过募集共激活因子（如 SRC1 和 CBP/p300）增强，并通过与核受体共抑制因子（NCoR 和 SMRT）结合而受到抑制。除了配体结合外，PPARα 的活性还受到翻译后修饰（如磷酸化和泛素化）的调节。在本报告中，我们证明 hPPARα 在铰链区的赖氨酸 185 上被 SUMO-1 进行 SUMO 化。E2 连接酶 Ubc9 和 SUMO E3 连接酶 PIASy 参与了这个过程。此外，配体处理降低了 hPPARα 的 SUMO 化速率。最后，我们的结果表明，hPPARα 的 SUMO-1 修饰通过特异性募集核受体共抑制因子 NCoR 而不是 SMRT 下调其转录活性，从而导致 PPARα 靶基因的亚组的差异表达。总之，hPPARα 在赖氨酸 185 上的 SUMO 化通过选择性募集 NCoR 下调其转录活性。
