RXRA
Domain
Composed of three domains: a modulating N-terminal domain (AF1 domain), a DNA-binding domain and a C-terminal ligand-binding domain (AF2 domain).
Function
Receptor for retinoic acid that acts as a transcription factor (PubMed:10874028, PubMed:11162439, PubMed:11915042, PubMed:37478846). Forms homo- or heterodimers with retinoic acid receptors (RARs) and binds to target response elements in response to their ligands, all-trans or 9-cis retinoic acid, to regulate gene expression in various biological processes (PubMed:10195690, PubMed:11162439, PubMed:11915042, PubMed:16107141, PubMed:17761950, PubMed:18800767, PubMed:19167885, PubMed:28167758, PubMed:37478846). The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 to regulate transcription (PubMed:10195690, PubMed:11162439, PubMed:11915042, PubMed:17761950, PubMed:28167758). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:1310260). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression (PubMed:20215566). On ligand binding, the corepressors dissociate from the receptors and coactivators are recruited leading to transcriptional activation (PubMed:20215566, PubMed:37478846, PubMed:9267036). Serves as a common heterodimeric partner for a number of nuclear receptors, such as RARA, RARB and PPARA (PubMed:10195690, PubMed:11915042, PubMed:28167758, PubMed:29021580). The RXRA/RARB heterodimer can act as a transcriptional repressor or transcriptional activator, depending on the RARE DNA element context (PubMed:29021580). The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes (PubMed:10195690). Together with RARA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). Acts as an enhancer of RARA binding to RARE DNA element (PubMed:28167758). May facilitate the nuclear import of heterodimerization partners such as VDR and NR4A1 (PubMed:12145331, PubMed:15509776). Promotes myelin debris phagocytosis and remyelination by macrophages (PubMed:26463675). Plays a role in the attenuation of the innate immune system in response to viral infections, possibly by negatively regulating the transcription of antiviral genes such as type I IFN genes (PubMed:25417649). Involved in the regulation of calcium signaling by repressing ITPR2 gene expression, thereby controlling cellular senescence (PubMed:30216632).
Post-translational modifications
Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity.
Phosphorylated on serine and threonine residues mainly in the N-terminal modulating domain (By similarity). Constitutively phosphorylated on Ser-21 in the presence or absence of ligand (By similarity). Under stress conditions, hyperphosphorylated by activated JNK on Ser-56, Ser-70, Thr-82 and Ser-260 (By similarity). Phosphorylated on Ser-27, in vitro, by PKA (PubMed:11162439). This phosphorylation is required for repression of cAMP-mediated transcriptional activity of RARA (PubMed:11162439).
Ubiquitinated by UBR5, leading to its degradation: UBR5 specifically recognizes and binds ligand-bound RXRA when it is not associated with coactivators (NCOAs) (PubMed:37478846). In presence of NCOAs, the UBR5-degron is not accessible, preventing its ubiquitination and degradation (PubMed:37478846).
Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6.
Sequence Similarities
Belongs to the nuclear hormone receptor family. NR2 subfamily.
Tissue Specificity
Expressed in lung fibroblasts (at protein level) (PubMed:30216632). Expressed in monocytes (PubMed:26463675). Highly expressed in liver, also found in kidney and brain (PubMed:14702039, PubMed:2159111, PubMed:24275569).
Cellular localization
- Nucleus
- Cytoplasm
- Mitochondrion
- Localization to the nucleus is enhanced by vitamin D3 (PubMed:15509776). Nuclear localization may be enhanced by the interaction with heterodimerization partner VDR (PubMed:12145331). Translocation to the mitochondrion upon interaction with NR4A1 (PubMed:15509776, PubMed:17761950). Increased nuclear localization upon pulsatile shear stress (PubMed:28167758).
Alternative names
NR2B1, RXRA, Retinoic acid receptor RXR-alpha, Nuclear receptor subfamily 2 group B member 1, Retinoid X receptor alpha