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

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.

A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder

“…In the absence of cognate retinoic acid ligands, RAR/RXR heterodimers are bound to nuclear receptor corepressors (NCoR) that keep the transcription of target genes off. Binding of ligands displaces the corepressors, allowing the recruitment of nuclear receptor co-activators (NCoA) to bind, resulting in the transcriptional activation of target genes [90] , [91] , [92] , [93] , [94] . In this way, retinoid-activated RAR/RXR signaling pathways directly or indirectly regulate hundreds of RARE-containing genes including Hox family genes, which are important in embryonic development, and genes important in the development and function of the immune system such as NF-κB, c-Myc, Lyn, IL2RA (interleukin 2 receptor-alpha subunit), and TGF-β (transforming growth factor-beta) [42] , [45] , [87] .…”

“…VDR can heterodimerize with RXR and bind to VDR elements (VDRE) on the target genes [321] , [322] . Binding of VitD to VDR/RXR heterodimers on the DNA recruits other regulatory factors to activate the transcription of the target genes [93] , [94] , [324] , [329] . In this way, the VitD signaling converges with that of VitA through the use of common RXR in modulating the expression of downstream genes [94] .…”

Vitamin A5/X controls stress-adaptation and prevents depressive-like behaviors in a mouse model of chronic stress

“…dimers which can be activated by RXR ligand. RXRs form such permissive heterodimers with for example NR4A2/Nurr1, PPARs, LXRs or FXRs ( Fadel et al, 2020 ; Krężel et al, 2021 ; Mangelsdorf et al, 1995 ). Although actual implication of RXR-mediated signaling in stress-related disorders remains to be investigated, we cannot exclude that chronic stress may directly decrease expression of specific RXRs, including RXRγ, or may negatively affect metabolism or transport of 9CDHROL or 9CDHRA.…”

Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function

“…The importance of RXRs; as master nuclear receptors, are derived from their ability to play a unique role as obligate heterodimerizing partners of many other nuclear receptors (110). In fact, there is different affinity and competition between RXR partners to form heterodimers with RXR (111). In addition to its role as transcription factor in the nucleus, activation of RXR may induce its translocation into the mitochondria, in order to enhance the transcription of mitochondrial genes (such as COX-1) (112).…”