ARNTL - Aryl hydrocarbon receptor nuclear translocator-like protein 1 - human protein (Function)
 
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ARNTL »  Aryl hydrocarbon receptor nuclear translocator-like protein 1
 
Protein also known as:  Class E basic helix-loop-helix protein 5 (bHLHe5).
Gene name:  ARNTL
Entry whose protein(s) existence is based on evidence at protein level
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1 84 9
GENE REF ISO

Function

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Overview 
Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. ARNTL/BMAL1 positively regulates myogenesis and negatively regulates adipogenesis via the transcriptional control of the genes of the canonical Wnt signaling pathway. Plays a role in normal pancreatic beta-cell function; regulates glucose-stimulated insulin secretion via the regulation of antioxidant genes NFE2L2/NRF2 and its targets SESN2, PRDX3, CCLC and CCLM. Negatively regulates the mTORC1 signaling pathway; regulates the expression of MTOR and DEPTOR. Controls diurnal oscillations of Ly6C inflammatory monocytes; rhythmic recruitment of the PRC2 complex imparts diurnal variation to chemokine expression that is necessary to sustain Ly6C monocyte rhythms. Regulates the expression of HSD3B2, STAR, PTGS2, CYP11A1, CYP19A1 and LHCGR in the ovary and also the genes involved in hair growth. Plays an important role in adult hippocampal neurogenesis by regulating the timely entry of neural stem/progenitor cells (NSPCs) into the cell cycle and the number of cell divisions that take place prior to cell-cycle exit. Regulates the circadian expression of CIART and KLF11. The CLOCK-ARNTL/BMAL1 heterodimer regulates the circadian expression of SERPINE1/PAI1, VWF, B3, CCRN4L/NOC, NAMPT, DBP, MYOD1, PPARGC1A, PPARGC1B, SIRT1, GYS2, F7, NGFR, GNRHR, BHLHE40/DEC1, ATF4, MTA1, KLF10 and also genes implicated in glucose and lipid metabolism. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by reducing the association of NR3C1/GR to glucocorticoid response elements (GREs) via the acetylation of multiple lysine residues located in its hinge region. Promotes rhythmic chromatin opening, regulating the DNA accessibility of other transcription factors. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina.  
7
  • UniProtKB
GO molecular function 
Aryl hydrocarbon receptor bindingdefinition[GO:0017162]  
1
  • BHF-UCL
bHLH transcription factor bindingdefinition[GO:0043425] silver  
1
  • Ortholog Compara
Core promoter bindingdefinition[GO:0001047]  
1
  • Ortholog Curator
Core promoter sequence-specific DNA bindingdefinition[GO:0001046] silver  
1
  • Ortholog Compara
DNA bindingdefinition[GO:0003677]  
2
  • UniProtKB
  • MGI
E-box bindingdefinition[GO:0070888]  
2
  • UniProtKB
Hsp90 protein bindingdefinition[GO:0051879]  
1
  • BHF-UCL
Protein bindingdefinition[GO:0005515]  
5
  • IntAct
  • UniProtKB
Protein heterodimerization activitydefinition[GO:0046982] silver  
1
  • Ortholog Compara
RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activitydefinition[GO:0000982]  
1
  • Ortholog Curator
RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcriptiondefinition[GO:0001190] silver  
1
  • Ortholog Compara
Sequence-specific DNA bindingdefinition[GO:0043565]  
1
  • Ortholog Curator
Signal transducer activitydefinition[GO:0004871] silver  
1
  • InterPro 2 GO
Transcription regulatory region sequence-specific DNA bindingdefinition[GO:0000976]  
1
  • Ortholog Curator
GO biological process 
Circadian regulation of gene expressiondefinition[GO:0032922]  
2
  • UniProtKB
  • Ortholog Curator
Negative regulation of fat cell differentiationdefinition[GO:0045599]  
1
  • Ortholog Curator
Negative regulation of glucocorticoid receptor signaling pathwaydefinition[GO:2000323]  
1
  • Ortholog Curator
Negative regulation of TOR signalingdefinition[GO:0032007]  
1
  • Ortholog Curator
Negative regulation of transcription, DNA-templateddefinition[GO:0045892]  
1
  • Ortholog Curator
Oxidative stress-induced premature senescencedefinition[GO:0090403]  
1
  • Ortholog Curator
Positive regulation of canonical Wnt signaling pathwaydefinition[GO:0090263]  
1
  • Ortholog Curator
Positive regulation of circadian rhythmdefinition[GO:0042753]  
1
  • Ortholog Curator
Positive regulation of skeletal muscle cell differentiationdefinition[GO:2001016]  
1
  • Ortholog Curator
Positive regulation of transcription from RNA polymerase II promoterdefinition[GO:0045944]  
2
  • BHF-UCL
  • MGI
Positive regulation of transcription, DNA-templateddefinition[GO:0045893]  
4
  • UniProtKB
Proteasome-mediated ubiquitin-dependent protein catabolic processdefinition[GO:0043161]  
1
  • Ortholog Curator
Protein import into nucleus, translocationdefinition[GO:0000060] silver  
1
  • Ortholog Compara
Regulation of cell cycledefinition[GO:0051726]  
1
  • Ortholog Curator
Regulation of cellular senescencedefinition[GO:2000772]  
1
  • Ortholog Curator
Regulation of hair cycledefinition[GO:0042634]  
1
  • UniProtKB
Regulation of insulin secretiondefinition[GO:0050796]  
1
  • Ortholog Curator
Regulation of neurogenesisdefinition[GO:0050767]  
1
  • Ortholog Curator
Regulation of protein catabolic processdefinition[GO:0042176] silver  
1
  • Ortholog Compara
Regulation of transcription, DNA-templateddefinition[GO:0006355]  
1
  • Ortholog Curator
Regulation of type B pancreatic cell developmentdefinition[GO:2000074]  
1
  • Ortholog Curator
Response to redox statedefinition[GO:0051775]  
1
  • UniProtKB
Signal transductiondefinition[GO:0007165] silver  
1
  • InterPro 2 GO
Spermatogenesisdefinition[GO:0007283]  
1
  • Ortholog Curator
Transcription from RNA polymerase II promoterdefinition[GO:0006366] silver  
1
  • Ortholog Compara
Enzymatic activity 
It is regulated in the following manner
The redox state of the cell can modulate the transcriptional activity of the CLOCK-ARNTL/BMAL1 and NPAS2-ARNTL/BMAL1 heterodimers; NADH and NADPH enhance the DNA-binding activity of the heterodimers.  
2
  • UniProtKB
Pathways 
According to KEGG, this protein belongs to the following pathways:
Circadian rhythm - mammal  hsa04710+406  
Dopaminergic synapse  hsa04728+406  
Herpes simplex infection  hsa05168+406  
According to Reactome, this protein belongs to the following pathways:
BMAL1:CLOCK,NPAS2 activates circadian gene expression  REACT_111118  
Circadian Clock  REACT_24941  
PPARA activates gene expression  REACT_116145  
REV-ERBA represses gene expression  REACT_118789  
RORA activates circadian gene expression  REACT_118659  
Note 
CLOCK-ARNTL/BMAL1 double mutations within the PAS domains result in synergistic desensitization to high levels of CRY on repression of CLOCK-ARNTL/BMAL1 transcriptional activity of PER1 and, disrupt circadian rhythmicity.  
1
  • UniProtKB
 

Keywords

Biological process 
Biological rhythms  definition   [KW-0090]
Transcription  definition   [KW-0804]
Transcription regulation  definition   [KW-0805]
Molecular function 
Activator  definition   [KW-0010]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

GeneWiki: ARNTL
GenomeRNAi: 406
PRO: PR:O00327