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

Lina Fadel, Bálint Rehó, Julianna Volkó, Dóra Bojcsuk, Zsuzsanna Kolostyák, Gergely Nagy, Gabriele Müller, Zoltan Simandi, Éva Hegedüs, Gábor Szabó, Katalin Tóth, Laszlo Nagy, György Vámosi

Research output: Contribution to journalArticlepeer-review

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 is directed by specific agonist treatment. Here, we tested this hypothesis on three NRs: peroxisome proliferator-activated receptor gamma (PPARγ), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARα). The 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 also might impede other NR pathways involving RXRα.

Original languageEnglish (US)
Pages (from-to)10045-10061
Number of pages17
JournalThe Journal of biological chemistry
Volume295
Issue number29
DOIs
StatePublished - Jul 17 2020

Keywords

  • ChIP sequencing (ChIP-seq)
  • confocal microscopy
  • dimerization
  • heterodimerization
  • nuclear receptor
  • nuclear receptors
  • nuclear transport
  • peroxisome proliferator‐activated receptor (PPAR)
  • retinoic acid receptor (RAR)
  • retinoid
  • retinoid X receptor (RXR)
  • transcription factor
  • transcription regulation
  • vitamin D
  • vitamin D receptor (VDR)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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