InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: NR1D1

Summary

InnateDB Protein

IDBP-47137.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

NR1D1

Protein Name

nuclear receptor subfamily 1, group D, member 1

Synonyms

ear-1; EAR1; hRev; THRA1; THRAL;

Species

Homo sapiens

Ensembl Protein

ENSP00000246672

InnateDB Gene

IDBG-47135 (NR1D1)

Protein Structure

UniProt Annotation

Function

Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. {ECO:0000269PubMed:12021280, ECO:0000269PubMed:15761026, ECO:0000269PubMed:16968709, ECO:0000269PubMed:18006707, ECO:0000269PubMed:19710360, ECO:0000269PubMed:1971514, ECO:0000269PubMed:21479263, ECO:0000269PubMed:22184247, ECO:0000269PubMed:2539258}.

Subcellular Localization

Nucleus. Cytoplasm {ECO:0000250}. Cell projection, dendrite {ECO:0000250}. Cell projection, dendritic spine {ECO:0000250}. Note=Localizes to the cytoplasm, dendrites and dendritic spine in the presence of OPHN1. {ECO:0000250}.

Disease Associations

Tissue Specificity

Widely expressed. Expressed at high levels in the liver, adipose tissue, skeletal muscle and brain. Also expressed in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and macrophages. Expression oscillates diurnally in the suprachiasmatic nucleus (SCN) of the hypothalamus as well as in peripheral tissues. Expression increases during the differentiation of pre-adipocytes into mature adipocytes. Expressed at high levels in some squamous carcinoma cell lines. {ECO:0000269PubMed:2539258}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 28 experimentally validated interaction(s) in this database.
They are also associated with 2 interaction(s) predicted by orthology.

Experimentally validated
Total	28 [view]
Protein-Protein	21 [view]
Protein-DNA	6 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	2 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0000978	RNA polymerase II core promoter proximal region sequence-specific DNA binding
GO:0001046	core promoter sequence-specific DNA binding
GO:0001078	RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in negative regulation of transcription
GO:0001222	transcription corepressor binding
GO:0003677	DNA binding
GO:0003700	sequence-specific DNA binding transcription factor activity
GO:0003707	steroid hormone receptor activity
GO:0003714	transcription corepressor activity
GO:0004879	ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity
GO:0005515	protein binding
GO:0008270	zinc ion binding
GO:0020037	heme binding
GO:0043565	sequence-specific DNA binding
GO:0044212	transcription regulatory region DNA binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0005978	glycogen biosynthetic process
GO:0006355	regulation of transcription, DNA-templated
GO:0006367	transcription initiation from RNA polymerase II promoter
GO:0007623	circadian rhythm
GO:0010467	gene expression
GO:0010498	proteasomal protein catabolic process
GO:0010871	negative regulation of receptor biosynthetic process
GO:0019216	regulation of lipid metabolic process
GO:0030154	cell differentiation
GO:0030522	intracellular receptor signaling pathway
GO:0032922	circadian regulation of gene expression
GO:0034144	negative regulation of toll-like receptor 4 signaling pathway
GO:0035947	regulation of gluconeogenesis by regulation of transcription from RNA polymerase II promoter
GO:0042752	regulation of circadian rhythm
GO:0043401	steroid hormone mediated signaling pathway
GO:0044321	response to leptin
GO:0045598	regulation of fat cell differentiation
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045893	positive regulation of transcription, DNA-templated
GO:0060086	circadian temperature homeostasis
GO:0061178	regulation of insulin secretion involved in cellular response to glucose stimulus
GO:0061469	regulation of type B pancreatic cell proliferation
GO:0070859	positive regulation of bile acid biosynthetic process
GO:0071222	cellular response to lipopolysaccharide
GO:2000188	regulation of cholesterol homeostasis

Cellular Component

GO:0000790	nuclear chromatin
GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005737	cytoplasm
GO:0030425	dendrite
GO:0043197	dendritic spine

Protein Structure and Domains

PDB ID

InterPro

IPR000536 Nuclear hormone receptor, ligand-binding, core
IPR001628 Zinc finger, nuclear hormone receptor-type
IPR001723 Steroid hormone receptor
IPR008946 Nuclear hormone receptor, ligand-binding

PFAM

PF00104
PF00105

PRINTS

PR00047
PR00398

PIRSF

SMART

SM00430
SM00399

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt