UniProt functional annotation for P28700



	UniProt functional annotation for P28700

UniProt code: P28700.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Receptor for retinoic acid that acts as a transcription factor (PubMed:10383391, PubMed:12032153, PubMed:25417649). 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:1310259, PubMed:10383391). 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:1310259). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:10383391, PubMed:25417649). 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 (By similarity). On ligand binding, the corepressors dissociate from the receptors and coactivators are recruited leading to transcriptional activation (By similarity). Serves as a common heterodimeric partner for a number of nuclear receptors, such as RARA, RARB and PPARA (PubMed:1310259). The RXRA/RARB heterodimer can act as a transcriptional repressor or transcriptional activator, depending on the RARE DNA element context (By similarity). The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes (By similarity). Together with RARA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (By similarity). Acts as an enhancer of RARA binding to RARE DNA element (By similarity). May facilitate the nuclear import of heterodimerization partners such as VDR and NR4A1 (By similarity). 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 (By similarity). {ECO:0000250|UniProtKB:P19793, ECO:0000269|PubMed:10383391, ECO:0000269|PubMed:12032153, ECO:0000269|PubMed:1310259, ECO:0000269|PubMed:25417649, ECO:0000269|PubMed:26463675}.

Subunit: Homodimer (By similarity). Heterodimer with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity (PubMed:10882070). Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity (By similarity). Heterodimerizes with PPARG (PubMed:7838715). Heterodimerizes (via NR LBD) with RARB (By similarity). Heterodimerizes with NR1H4; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (By similarity). Interacts with coactivator NCO6 (PubMed:10788465). Interacts with coactivator NCO3 (By similarity). Interacts with coactivator FAM120B (PubMed:17595322). Interacts with coactivator PELP1, SENP6, SFPQ, DNTTIP2 and RNF8 (By similarity). Interacts with PRMT2 (By similarity). Interacts with ASXL1 (PubMed:16606617). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2 (By similarity). Interacts in a ligand-dependent fashion with MED1 and NCOA1 (PubMed:15528208, PubMed:16606617). Interacts with VDR (By similarity). Interacts with EP300; the interaction is decreased by 9-cis retinoic acid (By similarity). Heterodimer (via C-terminus) with NR4A1 (via DNA-binding domain); the interaction is enhanced by 9-cis retinoic acid (By similarity). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250|UniProtKB:P19793, ECO:0000269|PubMed:10788465, ECO:0000269|PubMed:10882070, ECO:0000269|PubMed:15528208, ECO:0000269|PubMed:16606617, ECO:0000269|PubMed:17595322, ECO:0000269|PubMed:20078863, ECO:0000269|PubMed:7838715}.

Subcellular location: Nucleus {ECO:0000269|PubMed:26463675}. Cytoplasm {ECO:0000250|UniProtKB:P19793}. Mitochondrion {ECO:0000250|UniProtKB:P19793}. Note=Localization to the nucleus is enhanced by vitamin D3 (By similarity). Nuclear localization may be enhanced by the interaction with heterodimerization partner VDR (By similarity). Translocation to the mitochondrion upon interaction with NR4A1 (By similarity). Increased nuclear localization upon pulsatile shear stress (By similarity). {ECO:0000250|UniProtKB:P19793}.

Tissue specificity: Expressed in macrophages (at protein level). {ECO:0000269|PubMed:25417649, ECO:0000269|PubMed:26463675}.

Induction: Down-regulated by infection with viruses, such as VSV, HSV-1 and MHV68 (PubMed:25417649). Down-regulated by aging (PubMed:26463675). {ECO:0000269|PubMed:25417649, ECO:0000269|PubMed:26463675}.

Domain: Composed of three domains: a modulating N-terminal or AF1 domain, a DNA-binding domain and a C-terminal ligand-binding or AF2 domain.

Ptm: Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity. {ECO:0000250|UniProtKB:P19793}.

Ptm: Phosphorylated on serine and threonine residues mainly in the N- terminal modulating domain (PubMed:10383391, PubMed:12032153). Constitutively phosphorylated on Ser-22 in the presence or absence of ligand (PubMed:10383391, PubMed:12032153). Under stress conditions, hyperphosphorylated by activated JNK on Ser-61, Ser-75, Thr-87 and Ser- 265 (PubMed:10383391). Phosphorylated on Ser-28, in vitro, by PKA (By similarity). This phosphorylation is required for repression of cAMP- mediated transcriptional activity of RARA (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P19793, ECO:0000269|PubMed:10383391, ECO:0000269|PubMed:12032153}.

Ptm: Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6. {ECO:0000250|UniProtKB:P19793}.

Disruption phenotype: Reduced myelin debris uptake by bone marrow- derived macrophages (PubMed:26463675). Conditional knockout in myeloid cells results in reduced myelin debris clearing by macrophages, delayed oligodendrocyte progenitor cell differentiation and slowern remyelination after induced focal demyelination (PubMed:26463675). {ECO:0000269|PubMed:26463675}.

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

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Receptor for retinoic acid that acts as a transcription factor (PubMed:10383391, PubMed:12032153, PubMed:25417649). 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:1310259, PubMed:10383391). 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:1310259). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:10383391, PubMed:25417649). 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 (By similarity). On ligand binding, the corepressors dissociate from the receptors and coactivators are recruited leading to transcriptional activation (By similarity). Serves as a common heterodimeric partner for a number of nuclear receptors, such as RARA, RARB and PPARA (PubMed:1310259). The RXRA/RARB heterodimer can act as a transcriptional repressor or transcriptional activator, depending on the RARE DNA element context (By similarity). The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes (By similarity). Together with RARA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (By similarity). Acts as an enhancer of RARA binding to RARE DNA element (By similarity). May facilitate the nuclear import of heterodimerization partners such as VDR and NR4A1 (By similarity). 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 (By similarity). {ECO:0000250\|UniProtKB:P19793, ECO:0000269\|PubMed:10383391, ECO:0000269\|PubMed:12032153, ECO:0000269\|PubMed:1310259, ECO:0000269\|PubMed:25417649, ECO:0000269\|PubMed:26463675}.


Subunit:		Homodimer (By similarity). Heterodimer with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity (PubMed:10882070). Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity (By similarity). Heterodimerizes with PPARG (PubMed:7838715). Heterodimerizes (via NR LBD) with RARB (By similarity). Heterodimerizes with NR1H4; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (By similarity). Interacts with coactivator NCO6 (PubMed:10788465). Interacts with coactivator NCO3 (By similarity). Interacts with coactivator FAM120B (PubMed:17595322). Interacts with coactivator PELP1, SENP6, SFPQ, DNTTIP2 and RNF8 (By similarity). Interacts with PRMT2 (By similarity). Interacts with ASXL1 (PubMed:16606617). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2 (By similarity). Interacts in a ligand-dependent fashion with MED1 and NCOA1 (PubMed:15528208, PubMed:16606617). Interacts with VDR (By similarity). Interacts with EP300; the interaction is decreased by 9-cis retinoic acid (By similarity). Heterodimer (via C-terminus) with NR4A1 (via DNA-binding domain); the interaction is enhanced by 9-cis retinoic acid (By similarity). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250\|UniProtKB:P19793, ECO:0000269\|PubMed:10788465, ECO:0000269\|PubMed:10882070, ECO:0000269\|PubMed:15528208, ECO:0000269\|PubMed:16606617, ECO:0000269\|PubMed:17595322, ECO:0000269\|PubMed:20078863, ECO:0000269\|PubMed:7838715}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:26463675}. Cytoplasm {ECO:0000250\|UniProtKB:P19793}. Mitochondrion {ECO:0000250\|UniProtKB:P19793}. Note=Localization to the nucleus is enhanced by vitamin D3 (By similarity). Nuclear localization may be enhanced by the interaction with heterodimerization partner VDR (By similarity). Translocation to the mitochondrion upon interaction with NR4A1 (By similarity). Increased nuclear localization upon pulsatile shear stress (By similarity). {ECO:0000250\|UniProtKB:P19793}.
Tissue specificity:		Expressed in macrophages (at protein level). {ECO:0000269\|PubMed:25417649, ECO:0000269\|PubMed:26463675}.
Induction:		Down-regulated by infection with viruses, such as VSV, HSV-1 and MHV68 (PubMed:25417649). Down-regulated by aging (PubMed:26463675). {ECO:0000269\|PubMed:25417649, ECO:0000269\|PubMed:26463675}.
Domain:		Composed of three domains: a modulating N-terminal or AF1 domain, a DNA-binding domain and a C-terminal ligand-binding or AF2 domain.
Ptm:		Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity. {ECO:0000250\|UniProtKB:P19793}.
Ptm:		Phosphorylated on serine and threonine residues mainly in the N- terminal modulating domain (PubMed:10383391, PubMed:12032153). Constitutively phosphorylated on Ser-22 in the presence or absence of ligand (PubMed:10383391, PubMed:12032153). Under stress conditions, hyperphosphorylated by activated JNK on Ser-61, Ser-75, Thr-87 and Ser- 265 (PubMed:10383391). Phosphorylated on Ser-28, in vitro, by PKA (By similarity). This phosphorylation is required for repression of cAMP- mediated transcriptional activity of RARA (By similarity). {ECO:0000250, ECO:0000250\|UniProtKB:P19793, ECO:0000269\|PubMed:10383391, ECO:0000269\|PubMed:12032153}.
Ptm:		Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6. {ECO:0000250\|UniProtKB:P19793}.
Disruption phenotype:		Reduced myelin debris uptake by bone marrow- derived macrophages (PubMed:26463675). Conditional knockout in myeloid cells results in reduced myelin debris clearing by macrophages, delayed oligodendrocyte progenitor cell differentiation and slowern remyelination after induced focal demyelination (PubMed:26463675). {ECO:0000269\|PubMed:26463675}.
Similarity:		Belongs to the nuclear hormone receptor family. NR2 subfamily. {ECO:0000305}.