La proteína similar al translocador nuclear del receptor de hidrocarburos arilo 1 (ARNTL) o ARNT similar al cerebro y músculo 1 (BMAL1) es una proteína que en humanos está codificada por el gen Bmal1 , también conocido como ARNTL , MOP3 y, con menos frecuencia, BHLHE5 BMAL, BMAL1C, JAP3, PASD3 y TIC.
ARNTL | |||||||||||||||||||||||||
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Alias | ARNTL , BMAL1, BMAL1c, JAP3, MOP3, PASD3, TIC, bHLHe5, translocador nuclear del receptor de hidrocarburo de arilo como | ||||||||||||||||||||||||
Identificaciones externas | OMIM : 602550 MGI : 1096381 HomoloGene : 910 GeneCards : ARNTL | ||||||||||||||||||||||||
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Especies | Humano | Ratón | |||||||||||||||||||||||
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Ubicación (UCSC) | n / A | Crónicas 7: 113,21 - 113,31 Mb | |||||||||||||||||||||||
Búsqueda en PubMed | [2] | [3] | |||||||||||||||||||||||
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BMAL1 codifica un factor de transcripción con una hélice-bucle-hélice básica (bHLH) y dos dominios PAS . El gen Arntl humano tiene 24 exones predichos y está ubicado en la banda p15 del cromosoma 11 . [4] La proteína BMAL1 tiene 626 aminoácidos de longitud y juega un papel clave como uno de los elementos positivos en el ciclo de retroalimentación negativa de transcripción-traducción autorreguladora de mamíferos (TTFL), que es responsable de generar ritmos circadianos moleculares . La investigación ha revelado que Bmal1 es el único gen del reloj sin el cual el reloj circadiano no funciona en los seres humanos. [5] Bmal1 también se ha identificado como un gen candidato para la susceptibilidad a la hipertensión , la diabetes y la obesidad , [6] [7] y las mutaciones en Bmal1 se han relacionado con la infertilidad , problemas de gluconeogénesis y lipogénesis y patrones de sueño alterados . [8] Se estima que BMAL1, según el perfil de todo el genoma, se dirige a más de 150 sitios en el genoma humano, incluidos todos los genes del reloj y los genes que codifican proteínas que regulan el metabolismo. [9]
Historia
El gen Arntl fue descubierto originalmente en 1997 por dos grupos de investigadores, John B. Hogenesch et al. en marzo bajo el nombre de Mop3 [10] e Ikeda y Nomura en abril [11] como parte de una superfamilia de factores de transcripción de dominio PAS. [10] En 1998, la caracterización adicional de Hogenesch de MOP3 reveló que su papel como socio del factor de transcripción bHLH-PAS CLOCK era esencial para la función del reloj circadiano de los mamíferos. [12] Se descubrió que la proteína MOP3, como la conocía originalmente el grupo Hogenesch, se dimerizaba con MOP4, CLOCK y factores inducibles por hipoxia . [10] Los nombres BMAL1 y ARNTL fueron adoptados en artículos posteriores. Una de las primeras funciones descubiertas de la proteína ARNTL en la regulación circadiana estaba relacionada con el heterodímero CLOCK-BMAL1 (CLOCK-ARNTL) , que se uniría a través de un potenciador de caja E para activar la transcripción del gen AVP que codifica la vasopresina . [13] Sin embargo, la importancia del gen en los ritmos circadianos no se comprendió por completo hasta que la desactivación del gen en ratones mostró una pérdida completa de los ritmos circadianos en la locomoción y otros comportamientos. [14]
Genética
Regulación de la actividad Bmal1
SIRT1 regula la degradación de la proteína PER inhibiendo la actividad transcripcional del heterodímero BMAL1: CLOCK de forma circadiana a través de la desacetilación . [15] La degradación de las proteínas PER previene la formación del gran complejo proteico y, por lo tanto, desinhibe la actividad transcripcional del heterodímero BMAL1: CLOCK . La proteína CRY también recibe señales de degradación por poliubiquitinación de la proteína FBXL3, lo que da como resultado la desinhibición de la actividad del heterodímero BMAL1: CLOCK . [dieciséis]
Además del bucle TTFL regulador circadiano, Bmal1 transcripción está regulada por la unión competitiva al ácido retinoico -related receptor huérfano respuesta del sitio de unión al elemento-(RORE) dentro del promotor de Bmal1 . El heterodímero CLOCK / BMAL1 también se une a los elementos de la caja E en las regiones promotoras de los genes Rev-Erbα y RORα / ß, regulando positivamente la transcripción y traducción de las proteínas REV-ERB y ROR. Las proteínas REV-ERBα y ROR regulan la expresión de BMAL1 a través de un bucle de retroalimentación secundario y compiten para unirse a los elementos de respuesta Rev-Erb / ROR en el promotor Bmal1 , lo que da como resultado la expresión de BMAL1 reprimida por REV-ERBα y activada por proteínas ROR. También se ha demostrado que otros receptores nucleares de las mismas familias ( NR1D2 ( Rev-erb-β ); NR1F2 (ROR-β); y NR1F3 (ROR-γ)) actúan sobre la actividad transcripcional de Bmal1 de manera similar. [17] [18] [19] [20]
Varias modificaciones postraduccionales de BMAL1 dictan la sincronización de los bucles de retroalimentación CLOCK / BMAL1. La fosforilación de BMAL1 se dirige a la ubiquitinación y degradación, así como a la desubiquitinación y estabilización. La acetilación de BMAL1 recluta a CRY1 para suprimir la transactivación de CLOCK / BMAL1. [21] La sumoilación de BMAL1 por un pequeño modificador 3 relacionado con ubiquitina señala su ubiquitinación en el núcleo, lo que lleva a la transactivación del heterodímero CLOCK / BMAL1. [22] La transactivación de CLOCK / BMAL1, [23] es activada por fosforilación por la caseína quinasa 1ε e inhibida por la fosforilación por MAPK. [24] La fosforilación por CK2α regula la localización intracelular de BMAL1 [25] y la fosforilación por GSK3B controla la estabilidad de BMAL1 y la prepara para la ubiquitinación . [26]
En 2004, se descubrió que Rora era un activador de la transcripción de Bmal1 dentro del núcleo supraquiasmático (SCN), regulado por su reloj central. [27] Se encontró que Rora era necesario para la expresión normal de Bmal1 , así como para la consolidación de la actividad locomotora diaria. [27] Esto sugiere que las actividades opuestas de los receptores nucleares huérfanos RORA y REV-ERBα, el último de los cuales reprime la expresión de Bmal1 , son importantes en el mantenimiento de la función del reloj circadiano. [27] Actualmente, Rora está bajo investigación por su vínculo con el autismo , que puede ser una consecuencia de su función como regulador circadiano. [28]
Regulador / Modificador Bmal1 | Regulador positivo o negativo | Directo o indirecto | Mecanismo | Fuentes) |
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SIRT1 | Negativo | Directo | BMAL1: desacetilación del heterodímero CLOCK | [15] |
FBLX3 | Positivo | Indirecto | La poliubiquitinación de PER promueve la degradación de PER | [dieciséis] |
REV-ERBα / β | Negativo | Directo | Represión por la unión del promotor Bmal1 | [18] [19] [20] |
ROR-α / β / γ | Positivo | Directo | Activación mediante la unión del promotor Bmal1 | [17] [18] [19] [27] |
Acetilación | Negativo | Directo | Recluta CRY1 para inhibir el heterodímero BMAL1: CLOCK | [21] |
Modificador 3 pequeño relacionado con ubiquitina | Positivo | Directo | Sumoilación de BMAL1 | [22] |
Caseína quinasa 1ε | Positivo | Directo | Fosforilación del heterodímero CLOCK / BMAL1 | [23] |
MAPK | Positive | Direct | Phosphorylation of the CLOCK/BMAL1 heterodimer | [24] |
CK2α | Unclear | Direct | Phosphorylation of BMAL1 | [25] |
GSK3B | Positive | Direct | Phosphorylation of BMAL1 | [26] |
Species distribution
Along with mammals such as humans and mice, orthologs of the Arntl gene are also found in fish (AF144690.1),[29] birds (Arntl),[30] reptiles, amphibians (XI.2098), and Drosophila (Cycle, which encodes a protein lacking the homologous C-terminal domain, but still dimerizes with the CLOCK protein).[31] Unlike mammalian Arntl, circadian regulated, the Drosophila Cycle (gene) is constitutively expressed.[32] In humans, three transcript variants encoding two different isoforms have been found for this gene.[11] The importance of these transcript variants is unknown.
Mutations and disease
The Arntl gene is located within the hypertension susceptibility loci of chromosome 1 in rats. A study of single nucleotide polymorphisms (SNPs) within this loci found two polymorphisms that occurred in the sequence encoding for Arntl and were associated with type II diabetes and hypertension. When translated from a rat model to a human model, this research suggests a causative role of Arntl gene variation in the pathology of type II diabetes.[33] Recent phenotype data also suggest this gene[34] and its partner Clock[35] play a role in the regulation of glucose homeostasis and metabolism, which can lead to hypoinsulinaemia or diabetes when disrupted.[36]
In regards to other functions, another study shows that the CLOCK/BMAL1 complex upregulates human LDLR promoter activity, suggesting the Arntl gene also plays a role in cholesterol homeostasis.[37] Furthermore, BMAL1 has been shown to influence excitability and seizure threshold.[38] In addition, Arntl gene expression, along with that of other core clock genes, were discovered to be lower in patients with bipolar disorder, suggesting a problem with circadian function in these patients.[39] An SNP in Bmal1 was identified as having a link with bipolar disorder.[40] Arntl, Npas2, and Per2 have also been associated with seasonal affective disorder in humans.[41] Alzheimer's patients have different rhythms in BMAL1 methylation suggesting that its misregulation contributes to cognitive deficits.[42] Research has also shown that BMAL1 and other clock genes drive the expression of clock-controlled genes that are associated with Autism Spectrum Disorder (ASD).[43] Lastly, Arntl has been identified through functional genetic screening as a putative regulator of the p53 tumor suppressor pathway suggesting potential involvement in the circadian rhythms exhibited by cancer cells.[44]
In animal models of multiple sclerosis (MS), namely the experimental autoimmune encephalomyelitis (EAE) model, it has been shown that daily circadian rhythms can play an important role in disease pathology.[45] Inducing EAE through the active immunization of mice with myelin oligodendrocyte glycoprotein (MOG) peptide during the rest phase is more efficient in comparison to that during the active phase.[46] Disparity in EAE induction is critically dependent on BMAL1 expression in T cells and myeloid cells. T cell or myeloid-specific deletion of Bmal1 has been shown to cause more severe pathology and is sufficient to abolish the rest vs. active induction effect.[46]
Estructura
The BMAL1 protein contains fours domains according to its crystallographic structure: a bHLH domain, two PAS domains called PAS-A and PAS-B, and a trans-activating domain. The dimerization of CLOCK:BMAL1 proteins involves strong interactions between the bHLH, PAS A, and PAS B domains of both CLOCK and BMAL1 and forms an asymmetrical heterodimer with three distinct protein interfaces. The PAS-A interactions between CLOCK and BMAL1 involves an interaction, in which an α-helix of CLOCK PAS-A and the ß-sheet of BMAL1 PAS-A, and an α-helix motif of the BMAL1 PAS-A domain and the ß-sheet of CLOCK PAS-A.[47] CLOCK and BMAL1 PAS-B domains stack in a parallel fashion, resulting in the concealment of different hydrophobic residues on the ß-sheet of BMAL1 PAS-B and the helical surface of CLOCK PAS-B, such as Tyr 310 and Phe 423.[47] Key interactions with specific amino acid residues, specially CLOCK His 84 and BMAL1 Leu125, are important in the dimerization of these molecules.[48]
Función
Circadian Clock
The protein encoded by the Bmal1 gene in mammals binds with a second bHLH-PAS protein via the PAS domain, CLOCK (or its paralog, NPAS2) to form a heterodimer in the nucleus.[16] Via its BHLH domain, this heterodimer binds to E-box response elements[16] in the promoter regions of Per (Per1 and Per2) and Cry genes (Cry1 and Cry2).[16] This binding upregulates the transcription of Per1, Per2, Cry1 and Cry2 mRNAs.
After the PER and CRY proteins have accumulated to sufficient levels, they interact by their PAS motifs to form a large repressor complex that travels into the nucleus to inhibit the transcriptional activity of the CLOCK:BMAL1 heterodimer [49] This inhibits the heterodimer activation of the transcription of Per and Cry genes, and causes protein levels of PER and CRY drop. This transcription-translation negative feedback loop (TTFL) is modulated in the cytoplasm by phosphorylation of PER proteins by casein kinase 1ε or δ (CK1 ε or CK1 δ), targeting these proteins for degradation by the 26S proteasome.[16][50] The TTFL loop of nocturnal mice transcription levels of the Bmal1 gene peak at CT18, during the mid-subjective night, anti-phase to the transcription levels of Per, Cry, and other clock control genes, which peak at CT6, during the mid-subjective day. This process occurs with a period length of approximately 24 hours and supports the notion that this molecular mechanism is rhythmic.[51]
Estudios de knockout
The Arntl gene is an essential component within the mammalian clock gene regulatory network. It is a point of sensitivity within the network, as it is the only gene whose single knockout in a mouse model generates arrhythmicity at both the molecular and behavioral levels.[14] In addition to defects in the clock, these Arntl-null mice also have reproductive problems,[52] are small in stature, age quickly,[53] and have progressive arthropathy[54] that results in having less overall locomotor activity than wild type mice. However, recent research suggests that there might be some redundancy in the circadian function of Arntl with its paralog Bmal2.[55] BMAL1 KO is not embryonically lethal and mice with BMAL1 ablated in adulthood do not express the symptoms of BMAL1 KO mice.[56]
BMAL1 binding is regulated in a tissue-specific manner by numerous factors including non-circadian ones.[57] Following, tissue-specific KOs cause unique effects. BMAL1 has been shown to be important in bone metabolism as osteoblast BMAL1 KO mice have lower bone mass than their wild type counterparts.[58] It is also important for energy metabolism as BMAL1 modulates the regulation of hepatic metabolites, the secretion of insulin and proliferation of pancreatic islets, and adipocyte differentiation and lipogenesis.[42] Curiously, global KO of BMAL1 has no effect on food anticipatory activity (FAA) in mice but in BMAL1 deletions in certain regions in the hypothalamus outside the SCN eliminate FAA.[59] Knockout studies have demonstrated that BMAL1 is a key mediator between the circadian clock and the immune system response. By loss of Ccl2 regulation, BMAL1 KO in myeloid cells results in hindered monocyte recruitment, pathogen clearance, and anti-inflammatory response (consistent with the arthropathy phenotype).[60] Immune cells such as TNF-α and IL-1β reciprocally repress BMAL1 activity.[60] Finally, BMAL1 interactions with HSF1 triggers clock synchronization and the release of pro-survival factors, highlighting the contribution of BMAL1 to cell stress and survival responses.[61]
BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function.[62]
Interacciones
Arntl has been shown to interact with:
- Aryl hydrocarbon receptor[10]
- CLOCK[63][64][65]
- CREBBP[66][67]
- CRY1[67]
- EP300[67]
- EPAS1[63]
- HIF1A[63]
- NPAS2[63][65]
- SUMO3[22]
- BNIP3[62]
Ver también
- Arntl2 - Arntl2 (Bmal2) is a paralog of Arntl (Bmal1) that encodes for a basic helix-loop-helix PAS domain transcription factor. It, too, has been shown to play a circadian role, with its protein BMAL2 forming a transcriptionally active heterodimer with the CLOCK protein. It may also play a role in hypoxia.[68]
- Cycle - Cycle is the Drosophila melanogaster ortholog of Arntl.
Referencias
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enlaces externos
- Human ARNTL genome location and ARNTL gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: O00327 (Human Aryl hydrocarbon receptor nuclear translocator-like protein 1) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: Q9WTL8 (Mouse Aryl hydrocarbon receptor nuclear translocator-like protein 1) at the PDBe-KB.