NR1D2_MOUSE
ID NR1D2_MOUSE Reviewed; 576 AA.
AC Q60674; Q60646;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Nuclear receptor subfamily 1 group D member 2 {ECO:0000305};
DE AltName: Full=Orphan nuclear receptor RVR;
DE AltName: Full=Rev-erb-beta;
GN Name=Nr1d2 {ECO:0000312|MGI:MGI:2449205};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ; TISSUE=Brain;
RX PubMed=7838156; DOI=10.1210/mend.8.9.7838156;
RA Retnakaran R., Flock G., Giguere V.;
RT "Identification of RVR, a novel orphan nuclear receptor that acts as a
RT negative transcriptional regulator.";
RL Mol. Endocrinol. 8:1234-1244(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 35-576.
RC STRAIN=C57BL/6 X CBA; TISSUE=Liver;
RX PubMed=7838158; DOI=10.1210/mend.8.9.7838158;
RA Forman B.M., Chen J., Blumberg B., Kliewer S.A., Henshaw R., Ong E.,
RA Evans R.M.;
RT "Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear
RT receptors.";
RL Mol. Endocrinol. 8:1253-1261(1994).
RN [3]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=15623503; DOI=10.1074/jbc.m413949200;
RA Ramakrishnan S.N., Lau P., Burke L.J., Muscat G.E.;
RT "Rev-erbbeta regulates the expression of genes involved in lipid absorption
RT in skeletal muscle cells: evidence for cross-talk between orphan nuclear
RT receptors and myokines.";
RL J. Biol. Chem. 280:8651-8659(2005).
RN [4]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=18454201; DOI=10.1371/journal.pgen.1000023;
RA Liu A.C., Tran H.G., Zhang E.E., Priest A.A., Welsh D.K., Kay S.A.;
RT "Redundant function of REV-ERBalpha and beta and non-essential role for
RT Bmal1 cycling in transcriptional regulation of intracellular circadian
RT rhythms.";
RL PLoS Genet. 4:E1000023-E1000023(2008).
RN [5]
RP FUNCTION.
RX PubMed=19682428; DOI=10.1016/j.bbrc.2009.08.045;
RA Ramakrishnan S.N., Lau P., Crowther L.M., Cleasby M.E., Millard S.,
RA Leong G.M., Cooney G.J., Muscat G.E.;
RT "Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in
RT skeletal muscle cells.";
RL Biochem. Biophys. Res. Commun. 388:654-659(2009).
RN [6]
RP FUNCTION.
RX PubMed=22474260; DOI=10.1101/gad.186858.112;
RA Bugge A., Feng D., Everett L.J., Briggs E.R., Mullican S.E., Wang F.,
RA Jager J., Lazar M.A.;
RT "Rev-erbalpha and Rev-erbbeta coordinately protect the circadian clock and
RT normal metabolic function.";
RL Genes Dev. 26:657-667(2012).
RN [7]
RP FUNCTION, AND INDUCTION.
RX PubMed=23221024; DOI=10.5551/jat.14381;
RA Yang F., Inoue I., Kumagai M., Takahashi S., Nakajima Y., Ikeda M.;
RT "Real-time analysis of the circadian oscillation of the Rev-Erb beta
RT promoter.";
RL J. Atheroscler. Thromb. 20:267-276(2013).
RN [8]
RP FUNCTION.
RX PubMed=23728303; DOI=10.1038/nature12209;
RA Lam M.T., Cho H., Lesch H.P., Gosselin D., Heinz S., Tanaka-Oishi Y.,
RA Benner C., Kaikkonen M.U., Kim A.S., Kosaka M., Lee C.Y., Watt A.,
RA Grossman T.R., Rosenfeld M.G., Evans R.M., Glass C.K.;
RT "Rev-Erbs repress macrophage gene expression by inhibiting enhancer-
RT directed transcription.";
RL Nature 498:511-515(2013).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29355503; DOI=10.1016/j.bcp.2018.01.009;
RA Amador A., Kamenecka T.M., Solt L.A., Burris T.P.;
RT "REV-ERBbeta is required to maintain normal wakefulness and the wake-
RT inducing effect of dual REV-ERB agonist SR9009.";
RL Biochem. Pharmacol. 150:1-8(2018).
RN [10]
RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION BY CKSN1E.
RX PubMed=29508494; DOI=10.1111/gtc.12571;
RA Ohba Y., Tei H.;
RT "Phosphorylation of N-terminal regions of REV-ERBs regulates their
RT intracellular localization.";
RL Genes Cells 23:285-293(2018).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29533925; DOI=10.1172/jci93910;
RA Pariollaud M., Gibbs J.E., Hopwood T.W., Brown S., Begley N., Vonslow R.,
RA Poolman T., Guo B., Saer B., Jones D.H., Tellam J.P., Bresciani S.,
RA Tomkinson N.C., Wojno-Picon J., Cooper A.W., Daniels D.A., Trump R.P.,
RA Grant D., Zuercher W., Willson T.M., MacDonald A.S., Bolognese B.,
RA Podolin P.L., Sanchez Y., Loudon A.S., Ray D.W.;
RT "Circadian clock component REV-ERBalpha controls homeostatic regulation of
RT pulmonary inflammation.";
RL J. Clin. Invest. 128:2281-2296(2018).
RN [12]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29723273; DOI=10.1371/journal.pone.0196787;
RA Amador A., Campbell S., Kazantzis M., Lan G., Burris T.P., Solt L.A.;
RT "Distinct roles for REV-ERBalpha and REV-ERBbeta in oxidative capacity and
RT mitochondrial biogenesis in skeletal muscle.";
RL PLoS ONE 13:E0196787-E0196787(2018).
CC -!- FUNCTION: Transcriptional repressor which coordinates circadian rhythm
CC and metabolic pathways in a heme-dependent manner. Integral component
CC of the complex transcription machinery that governs circadian
CC rhythmicity and forms a critical negative limb of the circadian clock
CC by directly repressing the expression of core clock components
CC ARNTL/BMAL1 and CLOCK. Also regulates genes involved in metabolic
CC functions, including lipid metabolism and the inflammatory response.
CC Acts as a receptor for heme which stimulates its interaction with the
CC NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression.
CC Recognizes two classes of DNA response elements within the promoter of
CC its target genes and can bind to DNA as either monomers or homodimers,
CC depending on the nature of the response element. Binds as a monomer to
CC a response element composed of the consensus half-site motif 5'-
CC [A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a
CC homodimer to a direct repeat of the core motif spaced by two
CC nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR
CC alpha (RORA) function and also negatively regulates the expression of
CC NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle
CC via repression of genes involved in lipid metabolism and myogenesis
CC including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic
CC lipid metabolism via the repression of APOC3. Represses gene expression
CC at a distance in macrophages by inhibiting the transcription of
CC enhancer-derived RNAs (eRNAs). In addition to its activity as a
CC repressor, can also act as a transcriptional activator. Acts as a
CC transcriptional activator of the sterol regulatory element-binding
CC protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in
CC the skeletal muscle. Plays a role in the regulation of circadian
CC sleep/wake cycle; essential for maintaining wakefulness during the dark
CC phase or active period (PubMed:29355503). Key regulator of skeletal
CC muscle mitochondrial function; negatively regulates the skeletal muscle
CC expression of core clock genes and genes involved in mitochondrial
CC biogenesis, fatty acid beta-oxidation and lipid metabolism
CC (PubMed:29723273). May play a role in the circadian control of
CC neutrophilic inflammation in the lung (PubMed:29533925).
CC {ECO:0000269|PubMed:15623503, ECO:0000269|PubMed:18454201,
CC ECO:0000269|PubMed:19682428, ECO:0000269|PubMed:22474260,
CC ECO:0000269|PubMed:23221024, ECO:0000269|PubMed:23728303,
CC ECO:0000269|PubMed:29355503, ECO:0000269|PubMed:29533925,
CC ECO:0000269|PubMed:29723273}.
CC -!- ACTIVITY REGULATION: The heme-bound form can bind gaseous signaling
CC molecules such as CO and nitric oxide (NO) and NO can reverse its
CC transcriptional repressor activity. {ECO:0000250}.
CC -!- SUBUNIT: Binds DNA as a monomer or a homodimer (By similarity).
CC Interacts with NCOA5 coactivator, leading to a strong increase of
CC transcription of target genes (By similarity). Interacts (via N-
CC terminus) with KAT5 (By similarity). Interacts (via C-terminus) with
CC HDAC1 (By similarity). Interacts with ZNHIT1 (By similarity). Interacts
CC with SIAH2 (By similarity). {ECO:0000250|UniProtKB:Q14995}.
CC -!- INTERACTION:
CC Q60674; Q9HCD5: NCOA5; Xeno; NbExp=2; IntAct=EBI-5326205, EBI-2863498;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00407,
CC ECO:0000269|PubMed:29533925}. Cytoplasm {ECO:0000269|PubMed:29533925}.
CC Note=Phosphorylation by CSNK1E enhances its cytoplasmic localization.
CC {ECO:0000269|PubMed:29533925}.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Expressed abundantly in skeletal muscle
CC and brown adipose tissue. Expressed during skeletal muscle myogenesis.
CC {ECO:0000269|PubMed:15623503, ECO:0000269|PubMed:18454201}.
CC -!- INDUCTION: Activated by the CLOCK-ARNTL/BMLA1 heterodimer and DBP and
CC repressed by CRY1. {ECO:0000269|PubMed:23221024}.
CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain, a
CC DNA-binding domain and a C-terminal ligand-binding domain.
CC -!- PTM: Deacetylated by HDAC1 (By similarity). Acetylation and
CC deacetylation regulate its transcriptional regulatory activity (By
CC similarity). {ECO:0000250|UniProtKB:Q14995}.
CC -!- PTM: Under more reducing intracellular redox conditions, Cys-381 is in
CC its heme-bound state, which is optimal for recruitment of the
CC NCOR1/HDAC3 corepressor complex and repression of target genes (By
CC similarity). When subjected to oxidative stress conditions, Cys-381
CC undergoes oxidation to form a disulfide bridge with Cys-371, also
CC triggering a ligand switch that results in release of bound heme and
CC derepression of target genes (By similarity).
CC {ECO:0000250|UniProtKB:Q14995}.
CC -!- PTM: Ubiquitinated by SIAH2; leading to its proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q14995}.
CC -!- PTM: Phosphorylated by CSNK1E; phosphorylation enhances its cytoplasmic
CC localization. {ECO:0000269|PubMed:29533925}.
CC -!- DISRUPTION PHENOTYPE: Mice exhibit an altered circadian metabolism and
CC feeding schedule, eating more and utilizing more carbohydrates as fuel
CC during their nocturnal/sleep period (PubMed:29723273). Increased
CC expression of circadian clock core genes and genes involved in lipid
CC metabolism and fatty-acid oxidation in the skeletal muscle
CC (PubMed:29723273). Mice exhibit decreased wakefulness and increased
CC slow-wave sleep and rapid eye movement sleep during the dark phase
CC (active period) (PubMed:29355503). Altered expression in the brain of
CC core circadian clock genes and genes involved in sleep induction and
CC wakefulness (PubMed:29355503). Conditional knockout of both NR1D1 and
CC NR1D2 in bronchiolar epithelial cells abolished diurnal rhythmicity of
CC PER2 in the bronchioles and increased inflammatory responses and
CC chemokine activation (PubMed:29533925). {ECO:0000269|PubMed:29355503,
CC ECO:0000269|PubMed:29533925, ECO:0000269|PubMed:29723273}.
CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1
CC subfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U12142; AAA79513.1; -; mRNA.
DR EMBL; U09504; AAC52144.1; -; mRNA.
DR CCDS; CCDS36811.1; -.
DR PIR; A57048; A57048.
DR RefSeq; NP_035714.3; NM_011584.4.
DR AlphaFoldDB; Q60674; -.
DR SMR; Q60674; -.
DR BioGRID; 237266; 5.
DR IntAct; Q60674; 2.
DR MINT; Q60674; -.
DR STRING; 10090.ENSMUSP00000088031; -.
DR iPTMnet; Q60674; -.
DR PhosphoSitePlus; Q60674; -.
DR PaxDb; Q60674; -.
DR PRIDE; Q60674; -.
DR ProteomicsDB; 253009; -.
DR Antibodypedia; 11385; 343 antibodies from 31 providers.
DR DNASU; 353187; -.
DR Ensembl; ENSMUST00000090543; ENSMUSP00000088031; ENSMUSG00000021775.
DR GeneID; 353187; -.
DR KEGG; mmu:353187; -.
DR UCSC; uc007shp.2; mouse.
DR CTD; 9975; -.
DR MGI; MGI:2449205; Nr1d2.
DR VEuPathDB; HostDB:ENSMUSG00000021775; -.
DR eggNOG; KOG4846; Eukaryota.
DR GeneTree; ENSGT00940000155168; -.
DR HOGENOM; CLU_007368_2_4_1; -.
DR InParanoid; Q60674; -.
DR OMA; PASCHSD; -.
DR OrthoDB; 1240230at2759; -.
DR PhylomeDB; Q60674; -.
DR TreeFam; TF328382; -.
DR Reactome; R-MMU-383280; Nuclear Receptor transcription pathway.
DR BioGRID-ORCS; 353187; 1 hit in 72 CRISPR screens.
DR PRO; PR:Q60674; -.
DR Proteomes; UP000000589; Chromosome 14.
DR RNAct; Q60674; protein.
DR Bgee; ENSMUSG00000021775; Expressed in cerebellar vermis and 255 other tissues.
DR ExpressionAtlas; Q60674; baseline and differential.
DR Genevisible; Q60674; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:MGI.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0004879; F:nuclear receptor activity; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; ISO:MGI.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0048512; P:circadian behavior; IMP:UniProtKB.
DR GO; GO:0097009; P:energy homeostasis; IMP:UniProtKB.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0055088; P:lipid homeostasis; IMP:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; IDA:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IMP:UniProtKB.
DR GO; GO:2001014; P:regulation of skeletal muscle cell differentiation; IMP:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:MGI.
DR Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 1.
DR InterPro; IPR035500; NHR-like_dom_sf.
DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd.
DR InterPro; IPR001723; Nuclear_hrmn_rcpt.
DR InterPro; IPR001728; ThyrH_rcpt.
DR InterPro; IPR001628; Znf_hrmn_rcpt.
DR InterPro; IPR013088; Znf_NHR/GATA.
DR Pfam; PF00104; Hormone_recep; 1.
DR Pfam; PF00105; zf-C4; 1.
DR PRINTS; PR00398; STRDHORMONER.
DR PRINTS; PR00047; STROIDFINGER.
DR PRINTS; PR00546; THYROIDHORMR.
DR SMART; SM00430; HOLI; 1.
DR SMART; SM00399; ZnF_C4; 1.
DR SUPFAM; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Biological rhythms; Cytoplasm; Disulfide bond;
KW DNA-binding; Heme; Iron; Metal-binding; Nucleus; Phosphoprotein; Receptor;
KW Reference proteome; Repressor; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..576
FT /note="Nuclear receptor subfamily 1 group D member 2"
FT /id="PRO_0000053502"
FT DOMAIN 366..576
FT /note="NR LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189"
FT DNA_BIND 100..176
FT /note="Nuclear receptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 103..123
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT ZN_FING 140..164
FT /note="NR C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407"
FT REGION 1..99
FT /note="Modulating"
FT REGION 1..60
FT /note="Required for phosphorylation by CSNK1E and
FT cytoplasmic localization"
FT /evidence="ECO:0000269|PubMed:29533925"
FT REGION 13..90
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 215..246
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 263..282
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 394..576
FT /note="Interaction with ZNHIT1"
FT /evidence="ECO:0000250"
FT COMPBIAS 13..59
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 215..240
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 381
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /evidence="ECO:0000250"
FT BINDING 565
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /evidence="ECO:0000250"
FT MOD_RES 46
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250"
FT MOD_RES 162
FT /note="N6-acetyllysine; by KAT5"
FT /evidence="ECO:0000250|UniProtKB:Q14995"
FT MOD_RES 163
FT /note="N6-acetyllysine; by KAT5"
FT /evidence="ECO:0000250|UniProtKB:Q14995"
FT DISULFID 334..340
FT /evidence="ECO:0000250"
FT DISULFID 371..381
FT /evidence="ECO:0000250"
SQ SEQUENCE 576 AA; 64302 MW; 6620629052D2CD42 CRC64;
MELNAGGVIA YISSSSSASS PASCHSEGSE NSFQSSSSSV PSSPNSSNCD ANGNPKNADI
SSIDGVLKSD RTDCPVKTGK TSAPGMTKSH SGMTKFSGMV LLCKVCGDVA SGFHYGVHAC
EGCKGFFRRS IQQNIQYKKC LKNENCSIMR MNRNRCQQCR FKKCLSVGMS RDAVRFGRIP
KREKQRMLIE MQSAMKTMMN TQFSGHLQND TLAEQHDQSA LPAQEQLRPK SQLEQENIKN
TPSDFAKEEV IGMVTRAHKD TFLYNQEHRE NSSESMPPQR GERIPRNMEQ YNLNQDHRGS
GIHNHFPCSE RQQHLSGQYK GRNIMHYPNG HAVCIANGHC MNFSSAYTQR VCDRIPVGGC
SQTENRNSYL CNTGGRMHLV CPMSKSPYVD PQKSGHEIWE EFSMSFTPAV KEVVEFAKRI
PGFRDLSQHD QVNLLKAGTF EVLMVRFASL FDAKERTVTF LSGKKYSVDD LHSMGAGDLL
SSMFEFSEKL NALQLSDEEM SLFTAVVLVS ADRSGIENVN SVEALQETLI RALRTLIMKN
HPNEASIFTK LLLKLPDLRS LNNMHSEELL AFKVHP
