TY - JOUR
T1 - Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor
AU - Fadel, Lina
AU - Rehó, Bálint
AU - Volkó, Julianna
AU - Bojcsuk, Dóra
AU - Kolostyák, Zsuzsanna
AU - Nagy, Gergely
AU - Müller, Gabriele
AU - Simandi, Zoltan
AU - Hegedüs, Éva
AU - Szabó, Gábor
AU - Tóth, Katalin
AU - Nagy, Laszlo
AU - Vámosi, György
N1 - Funding Information:
Funding and additional information—This work was supported by the Stipendium Hungaricum Scholarship by the Tempus Public Foundation (to L. F.), NR-NET FP7-PEOPLE-2013-ITN-606806 Marie Curie Initial Training Networks (ITN) (to L. N. and L. F.), the National Research, Development, and Innovation Office grants NN129371, KKP129909, K124298, GINOP-2.3.2-15-2016-00026, and GINOP-2.3.3-15-2016-00003 (to G. V. and L. N.), the German Academic Exchange Service, and the Tempus Public Foundation no. 273478 (to G. V. and K. T).
Funding Information:
We thank Prof. John Schwabe (University of Leicester) and Dr. P?ter Vilmos for helpful discussions and Edina Nagy for technical assistance. Microscopy was carried out in the S?ndor Damjanovich Cell Analysis Core Facility of the University of Debrecen (Cellular BioImaging Hungary, a Euro-BioImaging Node). Funding and additional information-This work was supported by the Stipendium Hungaricum Scholarship by the Tempus Public Foundation (to L. F.), NR-NET FP7-PEOPLE-2013-ITN-606806 Marie Curie Initial Training Networks (ITN) (to L. N. and L. F.), the National Research, Development, and Innovation Office grants NN129371, KKP129909, K124298, GINOP-2.3.2-15-2016-00026, and GINOP-2.3.3-15-2016-00003 (to G. V. and L. N.), the German Academic Exchange Service, and the Tempus Public Foundation no. 273478 (to G. V. and K. T).
Publisher Copyright:
© 2020 Fadel et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020/7/17
Y1 - 2020/7/17
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.ra119.011614
DO - 10.1074/jbc.ra119.011614
M3 - Article
C2 - 32513869
AN - SCOPUS:85088493600
SN - 0021-9258
VL - 295
SP - 10045
EP - 10061
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -