Agonist Binding Directs Dynamic Competition Among Nuclear Receptors for Heterodimerization With Retinoid X Receptor

J Biol Chem. 2020 Jun 8;jbc.RA119.011614. doi: 10.1074/jbc.RA119.011614. Online ahead of print.

Abstract

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 may be directed by specific agonist treatment. Here, we tested this hypothesis on three NRs: peroxisome proliferator-activated receptor γ (PPARγ), vitamin D receptor (VDR), and retinoic acid receptor α (RARα). Evaluation of competition relied on a nuclear-translocation assay applied in a three-color imaging model system by detecting changes in heterodimerization between RXRα 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 RXRα and its partners in the following order: RARα>PPARγ>VDR. Second, upon agonist treatment, RXRα favors the liganded partner. We conclude that recruiting RXRα by the liganded NR not only facilitates a stimulus-specific cellular response, but might also impede other NR pathways involving RXRα.

Keywords: ChIP-sequencing (ChIP-seq); Retinoic Acid Receptor (RAR); Retinoid X Receptor (RXR); Vitamin D Receptor (VDR); confocal microscopy; dimerization; heterodimerization; nuclear receptor; nuclear transport; peroxisome proliferator-activated receptor (PPAR); retinoid; transcription factor; transcription regulation; vitamin D.