Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells

Dash, Amit Kumar; Yende, Ashutosh S.; Jaiswal, Bharti; Tyagi, Rakesh K.

doi:10.1016/j.yexcr.2017.09.024

Cited by 19 publications

(7 citation statements)

References 26 publications

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“…Based on our observations, we can conclude that mutation of the NLS1 of RXR partners increases their presence in the cytoplasm but retains their ability to heterodimerize with RXR and to bind their ligands effectively. In line with our results, NLS mutants of pregnane xenobiotic receptor and constitutive androstane receptor (CAR) also showed RXR heterodimerization-dependent nuclear import (36). These findings allowed us to establish the NLS1 mutant receptors as a good model to detect the occurrence of heterodimerization with RXR by using a translocation assay.…”

Section: Nls1 Mutants As a Model System To Study Heterodimerization With Rxrsupporting

confidence: 87%

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

Fadel

Rehó

Volkó

et al. 2020

Journal of Biological Chemistry

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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.

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Section: Nls1 Mutants As a Model System To Study Heterodimerization With Rxrsupporting

confidence: 87%

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

Fadel

Rehó

Volkó

et al. 2020

Journal of Biological Chemistry

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“…Another recent study suggested, however, that rather than taking place within the nucleus, heterodimerization of both CAR and PXR with RXR occurs within the cytoplasm. Dash and colleagues reported that nuclear entry of CAR-RXR and PXR-RXR heterodimers is dependent on the intact nuclear localization signal of at least one of the partners and is strongly influenced by the RXR nuclear localization signal (Zelko et al, 2001;Dash et al, 2017). Interestingly, these results contrast with interaction energy-based predictions from the aforementioned study, which would suggest that CAR-RXR heterodimerization would be favored over (and would thus preclude) CAR homodimerization in the cytoplasm if RXR were present.…”

Section: Constitutive Androstane Receptormentioning

confidence: 78%

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

et al. 2018

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Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.

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“…Sub-cellular localization of most of the steroid/nuclear receptors depends on the ligand binding, cell type, physiological state and nature of the interacting proteins [7]. NR-interacting proteins like coactivators and heterodimeric partners can also influence nuclear translocation of NRs [11,12]. NRs are also regulated by different posttranslational modifications (PTM) like phosphorylation, acetylation and sumoylation which may also alter sub-cellular localization.…”

Section: Dbd Lbdmentioning

confidence: 99%

“…CAR (Constitutive Androstane Receptor, NR1I3) has been reported to be localized predominantly in the cytoplasm with comparatively lower levels in the nucleus [12,40] by using GFPand RFP-tagged receptor in HEK-293T cell lines. The prediction methods (i.e.…”

Section: Nr1 Subfamilymentioning

confidence: 99%

A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors

Mathew¹,

Thakur²,

Kumar³

et al. 2018

Nuclear Receptor Research

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The Nuclear Receptor (NR) superfamily comprises of conserved ligand-modulated intracellular transcription factors which in the presence of their cognate ligands activate a plethora of signaling networks, thereby commencing their respective transcription functions. All NRs are nuclear when liganded or active. However, their localization may differ between nucleus and cytoplasm when unliganded or inactive. NRs control a majority of physiological processes in body ranging from metabolism to reproduction and development. Hitherto, in case of humans, 48 NRs have been identified which are localized either in cytosolic, nuclear or both compartments of the cell. Sub-cellular localization of proteins has great relevance in relation to their function. However, specific sub-cellular localization patterns of human NRs are clouded with ambiguity and are mostly ridden with controversy, with only a few of them being well-studied and established under specific physiological conditions. In the present study, we attempted to bridge the gap and attempted to draw conclusions in relation to sub-cellular localization of human NRs based on published experimental data and by in-silico prediction methods. This comprehensive analysis may not only be useful to draw conclusions on their control of physiological processes but may also open new avenues towards understanding of the molecular basis of NR-mediated diseases attributed to their mislocalization and malfunctioning.

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Heterodimerization of Retinoid X Receptor with Xenobiotic Receptor partners occurs in the cytoplasmic compartment: Mechanistic insights of events in living cells

Cited by 19 publications

References 26 publications

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

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

The Roles of Xenobiotic Receptors: Beyond Chemical Disposition

A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors

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