UniProt functional annotation for P19793



	UniProt functional annotation for P19793

UniProt code: P19793.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Receptor for retinoic acid that acts as a transcription factor (PubMed:11162439, PubMed:11915042). 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:28167758, PubMed:17761950, PubMed:16107141, PubMed:18800767, PubMed:19167885). 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: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). {ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:11162439, ECO:0000269|PubMed:11915042, ECO:0000269|PubMed:12145331, ECO:0000269|PubMed:1310260, ECO:0000269|PubMed:15509776, ECO:0000269|PubMed:16107141, ECO:0000269|PubMed:17761950, ECO:0000269|PubMed:18800767, ECO:0000269|PubMed:19167885, ECO:0000269|PubMed:20215566, ECO:0000269|PubMed:25417649, ECO:0000269|PubMed:26463675, ECO:0000269|PubMed:28167758, ECO:0000269|PubMed:29021580, ECO:0000269|PubMed:30216632, ECO:0000269|PubMed:9267036}.

Subunit: Homodimer (PubMed:10669605, PubMed:17761950). Heterodimer (via C-terminus) with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity; association with RARA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:15509776). Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity (PubMed:10195690, PubMed:11915042, PubMed:11698662). Heterodimerizes with PPARG (PubMed:10882139, PubMed:11698662). Heterodimerizes (via NR LBD) with RARB (PubMed:29021580). Heterodimerizes with NR1H4; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (PubMed:30275017). Interacts with NCOA3 and NCOA6 coactivators (PubMed:9267036, PubMed:10567404). Interacts with coactivator FAM120B (By similarity). Interacts with coactivator PELP1, SENP6, SFPQ, DNTTIP2 and RNF8 (PubMed:16574651, PubMed:16912044, PubMed:11259580, PubMed:15047147, PubMed:14981089). Interacts with PRMT2 (PubMed:12039952). Interacts with ASXL1 (By similarity). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2 (PubMed:19786558). Interacts in a ligand-dependent fashion with MED1 and NCOA1 (PubMed:19786558, PubMed:10882139, PubMed:11698662). Interacts with VDR (PubMed:28698609). Interacts with EP300; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). Heterodimer (via C-terminus) with NR4A1 (via DNA- binding domain); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250|UniProtKB:P28700, ECO:0000269|PubMed:10195690, ECO:0000269|PubMed:10567404, ECO:0000269|PubMed:10669605, ECO:0000269|PubMed:10698945, ECO:0000269|PubMed:10882139, ECO:0000269|PubMed:11259580, ECO:0000269|PubMed:11698662, ECO:0000269|PubMed:11915042, ECO:0000269|PubMed:12039952, ECO:0000269|PubMed:14981089, ECO:0000269|PubMed:15047147, ECO:0000269|PubMed:15509776, ECO:0000269|PubMed:16574651, ECO:0000269|PubMed:16912044, ECO:0000269|PubMed:17761950, ECO:0000269|PubMed:19786558, ECO:0000269|PubMed:20078863, ECO:0000269|PubMed:28167758, ECO:0000269|PubMed:28698609, ECO:0000269|PubMed:29021580, ECO:0000269|PubMed:30275017, ECO:0000269|PubMed:9267036}.

Subunit: (Microbial infection) Interacts (via the DNA binding domain) with HCV core protein; the interaction enhances the transcriptional activities of the RXRA/RARA and the RXRA/PPARA heterodimers. {ECO:0000269|PubMed:11915042}.

Subcellular location: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407, ECO:0000269|PubMed:11915042, ECO:0000269|PubMed:12145331, ECO:0000269|PubMed:15509776, ECO:0000269|PubMed:17761950, ECO:0000269|PubMed:28167758}. Cytoplasm {ECO:0000269|PubMed:12145331, ECO:0000269|PubMed:15509776}. Mitochondrion {ECO:0000269|PubMed:17761950}. Note=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:17761950, PubMed:15509776). Increased nuclear localization upon pulsatile shear stress (PubMed:28167758). {ECO:0000269|PubMed:12145331, ECO:0000269|PubMed:15509776, ECO:0000269|PubMed:17761950, ECO:0000269|PubMed:28167758}.

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:24275569, PubMed:2159111, PubMed:14702039). {ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:2159111, ECO:0000269|PubMed:24275569, ECO:0000269|PubMed:26463675, ECO:0000269|PubMed:30216632}.

Induction: Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758). {ECO:0000269|PubMed:26463675, ECO:0000269|PubMed:28167758}.

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).

Ptm: Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity. {ECO:0000269|PubMed:17761950}.

Ptm: 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). {ECO:0000250|UniProtKB:P28700, ECO:0000269|PubMed:11162439}.

Ptm: Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6. {ECO:0000269|PubMed:16912044}.

Similarity: Belongs to the nuclear hormone receptor family. NR2 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Receptor for retinoic acid that acts as a transcription factor (PubMed:11162439, PubMed:11915042). 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:28167758, PubMed:17761950, PubMed:16107141, PubMed:18800767, PubMed:19167885). 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: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). {ECO:0000269\|PubMed:10195690, ECO:0000269\|PubMed:11162439, ECO:0000269\|PubMed:11915042, ECO:0000269\|PubMed:12145331, ECO:0000269\|PubMed:1310260, ECO:0000269\|PubMed:15509776, ECO:0000269\|PubMed:16107141, ECO:0000269\|PubMed:17761950, ECO:0000269\|PubMed:18800767, ECO:0000269\|PubMed:19167885, ECO:0000269\|PubMed:20215566, ECO:0000269\|PubMed:25417649, ECO:0000269\|PubMed:26463675, ECO:0000269\|PubMed:28167758, ECO:0000269\|PubMed:29021580, ECO:0000269\|PubMed:30216632, ECO:0000269\|PubMed:9267036}.


Subunit:		Homodimer (PubMed:10669605, PubMed:17761950). Heterodimer (via C-terminus) with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity; association with RARA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:15509776). Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity (PubMed:10195690, PubMed:11915042, PubMed:11698662). Heterodimerizes with PPARG (PubMed:10882139, PubMed:11698662). Heterodimerizes (via NR LBD) with RARB (PubMed:29021580). Heterodimerizes with NR1H4; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (PubMed:30275017). Interacts with NCOA3 and NCOA6 coactivators (PubMed:9267036, PubMed:10567404). Interacts with coactivator FAM120B (By similarity). Interacts with coactivator PELP1, SENP6, SFPQ, DNTTIP2 and RNF8 (PubMed:16574651, PubMed:16912044, PubMed:11259580, PubMed:15047147, PubMed:14981089). Interacts with PRMT2 (PubMed:12039952). Interacts with ASXL1 (By similarity). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2 (PubMed:19786558). Interacts in a ligand-dependent fashion with MED1 and NCOA1 (PubMed:19786558, PubMed:10882139, PubMed:11698662). Interacts with VDR (PubMed:28698609). Interacts with EP300; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). Heterodimer (via C-terminus) with NR4A1 (via DNA- binding domain); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250\|UniProtKB:P28700, ECO:0000269\|PubMed:10195690, ECO:0000269\|PubMed:10567404, ECO:0000269\|PubMed:10669605, ECO:0000269\|PubMed:10698945, ECO:0000269\|PubMed:10882139, ECO:0000269\|PubMed:11259580, ECO:0000269\|PubMed:11698662, ECO:0000269\|PubMed:11915042, ECO:0000269\|PubMed:12039952, ECO:0000269\|PubMed:14981089, ECO:0000269\|PubMed:15047147, ECO:0000269\|PubMed:15509776, ECO:0000269\|PubMed:16574651, ECO:0000269\|PubMed:16912044, ECO:0000269\|PubMed:17761950, ECO:0000269\|PubMed:19786558, ECO:0000269\|PubMed:20078863, ECO:0000269\|PubMed:28167758, ECO:0000269\|PubMed:28698609, ECO:0000269\|PubMed:29021580, ECO:0000269\|PubMed:30275017, ECO:0000269\|PubMed:9267036}.
Subunit:		(Microbial infection) Interacts (via the DNA binding domain) with HCV core protein; the interaction enhances the transcriptional activities of the RXRA/RARA and the RXRA/PPARA heterodimers. {ECO:0000269\|PubMed:11915042}.
Subcellular location:		Nucleus {ECO:0000255\|PROSITE-ProRule:PRU00407, ECO:0000269\|PubMed:11915042, ECO:0000269\|PubMed:12145331, ECO:0000269\|PubMed:15509776, ECO:0000269\|PubMed:17761950, ECO:0000269\|PubMed:28167758}. Cytoplasm {ECO:0000269\|PubMed:12145331, ECO:0000269\|PubMed:15509776}. Mitochondrion {ECO:0000269\|PubMed:17761950}. Note=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:17761950, PubMed:15509776). Increased nuclear localization upon pulsatile shear stress (PubMed:28167758). {ECO:0000269\|PubMed:12145331, ECO:0000269\|PubMed:15509776, ECO:0000269\|PubMed:17761950, ECO:0000269\|PubMed:28167758}.
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:24275569, PubMed:2159111, PubMed:14702039). {ECO:0000269\|PubMed:14702039, ECO:0000269\|PubMed:2159111, ECO:0000269\|PubMed:24275569, ECO:0000269\|PubMed:26463675, ECO:0000269\|PubMed:30216632}.
Induction:		Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758). {ECO:0000269\|PubMed:26463675, ECO:0000269\|PubMed:28167758}.
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).
Ptm:		Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity. {ECO:0000269\|PubMed:17761950}.
Ptm:		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). {ECO:0000250\|UniProtKB:P28700, ECO:0000269\|PubMed:11162439}.
Ptm:		Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6. {ECO:0000269\|PubMed:16912044}.
Similarity:		Belongs to the nuclear hormone receptor family. NR2 subfamily. {ECO:0000305}.