Block of nuclear receptor ubiquitination. A mechanism of ligand-dependent control of peroxisome proliferator-activated receptor delta activity.

Peroxisome proliferator-activated receptor delta (PPARdelta) is a ligand-activated transcription factor involved in many physiological and pathological processes. PPARdelta is a promising therapeutic target for metabolic, chronic inflammatory, and neurodegenerative disorders. However, limited information is available about the mechanisms that control the activity of this nuclear receptor. Here, we examined the role of the ubiquitinproteasome system in PPARdelta turnover. The receptor was ubiquitinated and subject to rapid degradation by the 26 S proteasome. Unlike most nuclear receptors that are degraded upon ligand binding, PPARdelta ligands inhibited the ubiquitination of the receptor, thereby preventing its degradation. Ligand binding was required for inhibition of the ubiquitination since disruption of the ligand binding domain abolished the effect. Site-directed mutagenesis showed that the DNA binding domain was also required, indicating that ligands preferentially stabilized the DNA-bound receptor. In contrast, the activation function-2 domain and co-repressor binding site were not involved in ligand-induced stabilization. Block of ubiquitination by ligands may be an essential step to avoid rapid degradation of a receptor, like PPARdelta, with a very short half-life and sustain its transcriptional activity once it is engaged in transcriptional activation complexes.