Bcl3 Interacts Cooperatively with Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Coactivator 1α To Coactivate Nuclear Receptors Estrogen-Related Receptor α and PPARα

Estrogen-related receptors (ERRs) play critical roles in regulation of cellular energy metabolism in response to inducible coactivators such as peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERRalpha coactivator. Bcl3 was shown to synergize with PGC-1alpha to coactivate ERRalpha. Chromatin immunoprecipitation studies demonstrated that ERRalpha, PGC-1alpha, and Bcl3 form a complex on an ERRalpha-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1alpha and ERRalpha, allowing for interaction with both proteins. Transcriptional profiling demonstrated that Bcl3 activates genes involved in diverse pathways including a subset involved in cellular energy metabolism known to be regulated by PGC-1alpha, ERRalpha, and a second nuclear receptor, PPARalpha. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPARalpha with PGC-1alpha in a manner similar to ERRalpha. We propose that the cooperativity between Bcl3 and PGC-1alpha may serve as a point of convergence on nuclear receptor targets to direct programs orchestrating inflammatory and energy metabolism responses in heart and other tissues.