Heat shock protein-90 (Hsp90) acts as a repressor of peroxisome proliferator-activated receptor-α (PPARα) and PPARβ activity

摘要: The nuclear receptor (NR) peroxisome proliferator-activated receptor-alpha (PPARalpha) mediates the effects of several hypolipidemic drugs, endogenous fatty acids, and proliferators. Despite belonging to a class NR not known interact with cytosolic chaperone complexes, we have recently shown that PPARalpha interacts heat shock protein 90 (Hsp90), although biological consequence this association was unknown. In present study, directly associated Hsp90 in vitro much greater extent than either PPARbeta or PPARgamma. This interaction is similar other NR-Hsp90 complexes occurring between middle hinge (D) ligand binding domain (EF) PPARalpha. Using different approaches disrupt within cell, demonstrate repressor both activity. Treatment geldanamycin (GA) increased activity presence transient transfection assays. PPARalpha-response element (PPRE)-reporter assays stable cell line treated GA resulted enhanced expression target gene, acyl-CoA oxidase. Similarly, overexpression tetratricopeptide repeat (TPR) phosphatase 5 (PP5) PPRE-reporter assay decreased mammalian two-hybrid assay. Finally, cotransfection C-terminal hsp-interacting (CHIP) construct, TPR-containing ubiquitin ligase hsp90, PPARalpha's PPARbeta's ability regulate upon activation. All three methods function (GA, PP5-TPR, CHIP) an alteration While FKBP52 had no effect on activity, p23 greatly constitutive Wy14 643 induced Thus, describe complex as being regulator identified novel, subtype-specific, inhibitory role for Hsp90.