ReviewAlternative retinoid X receptor (RXR) ligands
Introduction
Retinoid X receptors discovered in the early 1990s (Leid et al., 1992; Mangelsdorf et al., 1992) are nuclear hormone receptors (NRs) acting as transcription factors, which in mammals are represented by three isoforms, RXRα, β, and γ (named also NR2B1, 2 and 3 (Germain et al., 2006b). These are encoded by distinct genes (9q34.3, 6p21.1–3, 1q22-23, respectively) displaying different expression patterns (Dolle et al., 1994; Krezel et al., 1999; Mori et al., 2001). RXRs are exceptional in the sense that they can act as homodimers, but also as obligatory heterodimerization partners for different types of NRs including: (i) classical hormone receptors like thyroid receptors (TRα, β; NR1A1, 2), vitamin D receptor (VDR; NR1I1) and retinoic acid receptors (RARα, β, γ; NR1B1, 2, 3), (ii) metabolite or drug sensor receptors such as peroxisome proliferator activated receptors (PPARα, β/δ, γ; NR1C1, 2, 3), liver X receptor (LXRα, β; NR1H2, 3), farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; N1I2) and (iii) orphan receptors like Nur77 (NR4A1), Nurr1 (NR4A2) and constitutive androgen receptor (CAR; NRI3). Hence RXRs bridge different signaling pathways whereby they can: (i) act as “silent” partners of “non-permissive” NRs (TRs, VDR), being insensitive to their own ligand in different biological settings (Forman et al., 1995; Thompson et al., 1998), (ii) enhance activity in a ligand-dependent manner of ligand-activated “conditional” partners (RARs and in case of colon cancer or endothelial cells also VDR), here not being able to induce NR/RXR activity on their own (Germain et al., 2006a; Lin et al., 2016; Sanchez-Martinez et al., 2006), and (iii) induce activity of “permissive” heterodimerization partners (PPARs, LXRs, FXR, Nurr1, Nur77) upon binding of RXR ligand (Forman et al., 1995; Germain et al., 2006a; Giner et al., 2015). Importantly, RXR heterodimers with PPARs, LXRs, FXR can also be activated by respective ligands of the RXR partner. On the other hand, RXR ligand remains the only mean to activate heterodimers with orphan receptors or RXR homodimers (see Fig. 1). Such promiscuity of RXRs can be critical for harmonized tuning of physiologic programs necessary for adaptive process, but also re-adjustment of the transcriptional programs under pathological conditions, as reflected by clinical or experimental data for some RXR ligands discussed below. Knowledge on RXR architecture and its dynamics is essential for understanding of ligand binding mechanisms and their functional outcome. Here, we will first review RXR structural data focusing much on those that are relevant for binding of different ligands. In contrast to previous reviews on RXRs and their ligands (named rexinoids) which focused much on structural biology, molecular functions and post-transcriptional modulation of RXR functions (Dawson and Xia, 2012), or modulation of metabolic receptors (Hiebl et al., 2018), we will put particular emphasis on known endogenous ligands and their metabolites. The physiological relevance of such ligands will be discussed with its functional and nutritional perspectives. In particular, 9-cis-retinoic acid (9CRA), formerly widely accepted as the potential physiological RXR ligand, was found to be essentially undetectable under physiological conditions in vertebrates including human serum and tissue samples. We will review evidence indicating that 9-cis-13,14-dihydroretinoic acid (9CDHRA) meets probably best the criterion of a physiological ligand of RXRs. The physiological relevance of 9CDHRA is further supported by its central role in the concept of vitamin A5, identified as a new class of vitamin A, which may depend on a distinct set of nutritionally relevant precursors. This does not exclude the possibility that other endogenous ligands might also be physiologically and nutritionally relevant in specific cell types or in some “challenging” conditions such as nutritional deficits of specific micronutrients, as reviewed below. Characterization of the physiological relevance of any ligand remains both a conceptual and technological challenge, which may require development of new approaches, as discussed below. Additional review of natural phyto-rexinoids, environmental pollutants and synthetic ligands highlights the high diversity of their chemical structures, and thereby of possible mechanisms of ligand binding and transcriptional regulatory activity.
Finally, despite such a diversity, studies of ancestral RXRs point to particular evolutionary pressure to maintain ligand binding for these receptors, and agonistic effect of such interaction. We will thus discuss the potential physiological and nutritional relevance of endogenous RXR ligand evolution. Characterization of such ligand(s), and their genomic and functional effects, may help to define core, ancient RXR functions and understand how ligand-dependent control of RXR functions could provide evolutionary advantage.
Section snippets
The structure of retinoid X receptors
Similarly to other nuclear receptors, RXRs display a domain-like organization with a variable N-terminal domain (NTD) followed by a highly conserved DNA binding domain (DBD) connected by a hinge region with the C-terminal ligand binding (LBD) domain. Although isolated domains display intrinsic activities, such as DNA binding for DBD or ligand binding for LBD, their interactions within the entire receptor are highly dynamic and are under control of multiple allosteric modulators, which underlie
Natural ligands of RXRs and their potential physiological relevance
Before discussing different types of ligands, we need first to define concepts of natural vs endogenous and physiological ligands, which are frequently misused. We will thus consider as natural ligands all substances present in Nature that bind with high potency (optimally in the nanomolar range) their receptors leading to conformational changes in the receptor structure, and induce relevant physiological functions. Excluded are all man-made compounds generated de novo, which will be referred
Synthetic ligands
The design of synthetic ligands was much instructed by the chemical structures of endogenous ligands, the structure of RXR LBD and data on ligand – LBD interactions. Inversely, challenging RXR LBD with such ligands and millions of molecules in silico and in functional screens followed by determination of their structure-activity relationship (SAR), and sometimes even crystal structure, was highly informative about: (i) flexibility of LBD in binding different compounds, (ii) how such flexibility
Evolutionary considerations
To better understand the origins but also the functional relevance of ligand-dependent regulation of RXRs in vertebrates, we need to travel in time a billion years backwards and look into the evolution of RXRs, their ligands and their functions. Phylogenetic analyses identified an RXR ancestral gene in Placozoans (Baker, 2008; Srivastava et al., 2008) and Cnidarians (Fuchs et al., 2014; Kostrouch et al., 1998), the simplest multicellular organisms and most ancient animal lineages. In
Conclusions and future directions
Since the initial identification of 9CRA as an agonist of RXR and the demonstration that RXR homo- and heterodimers can be modulated by RXR ligands, much research has been performed to dissect their physiological and biological relevance, and the molecular mechanisms of ligand-dependent RXR control. Investigation of natural and synthetic RXR ligands have been very fruitful in revealing the high diversity of ligand binding modes and the possibility of specific/selective activation of certain
Acknowledgements
Research in WK laboratory was funded by a grant from University of Strasbourg Institute for Advanced Study (USIAS) and by an institutional grant (LabEx ANR-10-LABX-0030-INRT) under the frame programme Investissements d’Avenir IDEX (ANR-10-IDEX-0002-02). Work in ARdL laboratory was supported by the Spanish MINECO (SAF2016-77620-R-FEDER) and Xunta de Galicia (Consolidación GRC ED431C 2017/61 from DXPCTSUG; ED-431G/02-FEDER “Unha maneira de facer Europa” to CINBIO, a Galician research center
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