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

摘要

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 (PPARγ) coactivator 1α (PGC-1α). A yeast two-hybrid screen led to the identification of the cytokine-stimulated transcriptional regulator, Bcl3, as an ERRα coactivator. Bcl3 was shown to synergize with PGC-1α to coactivate ERRα. Chromatin immunoprecipitation studies demonstrated that ERRα, PGC-1α, and Bcl3 form a complex on an ERRα-responsive element within the pyruvate dehydrogenase kinase 4 gene promoter in cardiac myocytes. Mapping studies demonstrated that Bc13 interacts with PGC-1α and ERRα, 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-1α, ERRα, and a second nuclear receptor, PPARα. Consistent with the gene expression profiling results, Bcl3 was shown to synergistically coactivate PPARα with PGC-1α in a manner similar to ERRα. We propose that the cooperativity between Bcl3 and PGC-1α 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.