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

Lina Fadel1, Bálint Rehó1, Julianna Volkó1

  • 1Department of Biophysics and Cell Biology, Doctoral School of Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

The Journal of Biological Chemistry
|June 10, 2020
PubMed

Insights

Nuclear receptors (NRs) compete for Retinoid X Receptor (RXR) binding. Agonist treatment directs this competition, with RXR favoring liganded partners, impacting cellular responses and other NR pathways.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Endocrinology

Background:

  • Retinoid X receptor (RXR) is a crucial transcriptional regulator and partners with over 20 other nuclear receptors (NRs).
  • A limited pool of RXR suggests potential competition among its various partners for binding.
  • This competition may be modulated by specific agonist treatments.

Purpose of the Study:

  • To investigate the hypothesis that NRs compete for RXR binding.
  • To determine if agonist treatment directs this competition.
  • To examine the competitive dynamics between RXRα and its partners: peroxisome proliferator-activated receptor gamma (PPARγ), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARα).

Main Methods:

  • Utilized a three-color imaging model system.
  • Employed a nuclear translocation assay to detect changes in heterodimerization.
  • Assessed heterodimerization between RXRα and one partner (NR1) in the presence of a competing partner (NR2).

Main Results:

  • Demonstrated dynamic competition between NRs for RXRα binding.
  • Established a hierarchy of affinities in the absence of agonists: RARα > PPARγ > VDR.
  • Showed that RXRα preferentially binds to the liganded partner upon agonist treatment.

Conclusions:

  • NR competition for RXRα is governed by affinity hierarchies and agonist-induced preferences.
  • Liganded NR recruitment of RXRα ensures stimulus-specific cellular responses.
  • This process may also inhibit other RXRα-dependent NR pathways.
Keywords:
ChIP sequencing (ChIP-seq)confocal microscopydimerizationheterodimerizationnuclear receptornuclear receptorsnuclear transportperoxisome proliferator‐activated receptor (PPAR)retinoic acid receptor (RAR)retinoidretinoid X receptor (RXR)transcription factortranscription regulationvitamin Dvitamin D receptor (VDR)

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