Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor

Retinoid X receptor (RXR) plays a pivotal role as a transcriptional regulator and serves as an obligatory heterodimerization partner for at least 20 other nuclear receptors (NRs). Given a potentially limiting/sequestered pool of RXR and simultaneous expression of several RXR partners, we hypothesized that NRs compete for binding to RXR and that this competition is directed by specific agonist treatment. Here, we tested this hypothesis on three NRs: peroxisome proliferator-activated receptor gamma (PPARg), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARa). The evaluation of competition relied on a nuclear translocation assay applied in a three-color imaging model system by detecting changes in heterodimerization between RXRa and one of its partners (NR1) in the presence of another competing partner (NR2). Our results indicated dynamic competition between the NRs governed by two mechanisms. First, in the absence of agonist treatment, there is a hierarchy of affinities between RXRa and its partners in the following order: RARa > PPARg > VDR. Second, upon agonist treatment, RXRa favors the liganded partner. We conclude that recruiting RXRa by the liganded NR not only facilitates a stimulus-specific cellular response but also might impede other NR pathways involving RXRa.