NR1D1

This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

Nuclear Receptor Subfamily 1 Group D Member 1

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 G6PC1 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. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity).
Represses the transcription of CES2 (By similarity).
Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity).
Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity).
Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity).
Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity).
Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity).

Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cellular glucose homeostasisManual Assertion Based On ExperimentIMP:UniProtKB
Cellular response to interleukin-1ISS:UniProtKB
Cellular response to lipopolysaccharideManual Assertion Based On ExperimentIMP:BHF-UCL
Cellular response to tumor necrosis factorISS:UniProtKB
Cholesterol homeostasisISS:UniProtKB
Circadian regulation of gene expressionISS:UniProtKB
Circadian temperature homeostasisISS:UniProtKB
Glycogen biosynthetic processISS:UniProtKB
Hormone-mediated signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Negative regulation of astrocyte activationISS:UniProtKB
Negative regulation of cold-induced thermogenesisBy SimilarityISS:YuBioLab
Negative regulation of I-kappaB kinase/NF-kappaB signalingISS:UniProtKB
Negative regulation of inflammatory responseISS:UniProtKB
Negative regulation of microglial cell activationISS:UniProtKB
Negative regulation of neuroinflammatory responseISS:UniProtKB
Negative regulation of toll-like receptor 4 signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIDA:NTNU_SB
Negative regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of bile acid biosynthetic processISS:UniProtKB
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of transcription, DNA-templatedISS:UniProtKB
Proteasomal protein catabolic processISS:UniProtKB
Protein destabilizationISS:UniProtKB
Regulation of circadian rhythmISS:UniProtKB
Regulation of circadian sleep/wake cycleISS:UniProtKB
Regulation of fat cell differentiationISS:UniProtKB
Regulation of insulin secretion involved in cellular response to glucose stimulusISS:UniProtKB
Regulation of lipid metabolic processISS:UniProtKB
Regulation of type B pancreatic cell proliferationISS:UniProtKB
Response to leptinISS:UniProtKB

Nucleus
Cytoplasm
Cell projection, dendrite
Cell projection, dendritic spine
Localizes to the cytoplasm, dendrites and dendritic spine in the presence of OPHN1. Localizes predominantly to the nucleus at ZT8 whereas it is cytoplasmic at ZT20. Phosphorylation by CSNK1E enhances its cytoplasmic localization.

Ubiquitinated, leading to its proteasomal degradation (PubMed:16484495, PubMed:23398316, PubMed:20534529).
Ubiquitinated by SIAH2; leading to its proteasomal degradation (PubMed:26392558).
Ubiquitinated by the SCF(FBXW7) complex when phosphorylated by CDK1 leading to its proteasomal degradation (By similarity).
Rapidly ubiquitinated in response to inflammatory triggers and sumoylation is a prerequisite to its ubiquitination (By similarity).
Sumoylated by UBE2I, desumoylated by SENP1, and sumoylation is a prerequisite to its ubiquitination.
Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic localization.
Undergoes lysosome-mediated degradation in a time-dependent manner in the liver.