Cytosolic BMAL1 moonlights as a translation factor

Michael, Alicia K.; Asimgil, Hande; Partch, Carrie L.

doi:10.1016/j.tibs.2015.07.006

Cited by 8 publications

(8 citation statements)

References 10 publications

(14 reference statements)

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“…Indeed, BMAL1 carries nuclear localization (NLS) and nuclear export (NES) signals [24], and when all cytoplasmic signals were repeatedly bleached in living cells, there was a drop of nuclear Venus::BMAL1 signal, as shown by fluorescence loss in photobleaching (FLIP) (S4G and S4H Fig) in both fibroblasts (15.1 ±6.1%, n = 3) and chondrocytes (21.7 ±3.3%, n = 3), indicating that even though Venus::BMAL1 is predominantly nuclear, it does shuttle from nucleus to cytoplasm. Key functions of cytoplasmic BMAL1 include its hetero-dimerisation with CLOCK, which is reported as essential for the phosphorylation and nuclear accumulation of CLOCK, and the proteolysis of CLOCK/BMAL1 heterodimers [8,9,25]. Taken together, our live imaging data and FLIP analysis clearly indicate tight spatial and temporal control of BMAL1 localisation during daily and cell-division cycles.…”

Section: Plos Geneticssupporting

confidence: 56%

“…As such, BMAL1 knockout has been widely used as a model for molecular disruption of circadian rhythms, revealing essential, tissue-specific roles of BMAL1 in, for example, the brain, liver and the musculoskeletal system [6,7]. Moreover, BMAL1 has clock-independent functions that influence ageing and protein translation [8,9]. Despite this key importance, direct measures of the intra-cellular behaviour of BMAL1 in central and peripheral clocks are still lacking.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative live imaging of Venus::BMAL1 in a mouse model reveals complex dynamics of the master circadian clock regulator

et al. 2020

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Evolutionarily conserved circadian clocks generate 24-hour rhythms in physiology and behaviour that adapt organisms to their daily and seasonal environments. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the principal coordinator of the cellautonomous clocks distributed across all major tissues. The importance of robust daily rhythms is highlighted by experimental and epidemiological associations between circadian disruption and human diseases. BMAL1 (a bHLH-PAS domain-containing transcription factor) is the master positive regulator within the transcriptional-translational feedback loops (TTFLs) that cell-autonomously define circadian time. It drives transcription of the negative regulators Period and Cryptochrome alongside numerous clock output genes, and thereby powers circadian time-keeping. Because deletion of Bmal1 alone is sufficient to eliminate circadian rhythms in cells and the whole animal it has been widely used as a model for molecular disruption of circadian rhythms, revealing essential, tissue-specific roles of BMAL1 in, for example, the brain, liver and the musculoskeletal system. Moreover, BMAL1 has clock-independent functions that influence ageing and protein translation. Despite the essential role of BMAL1 in circadian time-keeping, direct measures of its intra-cellular behaviour are still lacking. To fill this knowledge-gap, we used CRISPR Cas9 to generate a mouse expressing a knock-in fluorescent fusion of endogenous BMAL1 protein (Venus::BMAL1) for quantitative live imaging in physiological settings. The Bmal1 Venus mouse model enabled us to visualise and quantify the daily behaviour of this core clock factor in central (SCN) and peripheral clocks, with single-cell resolution that revealed its circadian expression, anti-phasic to negative regulators, nuclear-cytoplasmic mobility and molecular abundance.

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Section: Plos Geneticssupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Quantitative live imaging of Venus::BMAL1 in a mouse model reveals complex dynamics of the master circadian clock regulator

et al. 2020

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“…The subcellular distribution of the bHLH-PAS proteins is one of mechanisms regulating their functions and activities. Recently it was shown, that in addition to functioning as transcriptional regulators, some of bHLH-PAS transcription factors, when located in cytoplasm, take part in regulation of translational processes [110,111,112].…”

Section: Discussionmentioning

confidence: 99%

Subcellular Localization Signals of bHLH-PAS Proteins: Their Significance, Current State of Knowledge and Future Perspectives

Greb‐Markiewicz

Kolonko

2019

IJMS

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The bHLH-PAS (basic helix-loop-helix/ Period-ARNT-Single minded) proteins are a family of transcriptional regulators commonly occurring in living organisms. bHLH-PAS members act as intracellular and extracellular “signals” sensors, initiating response to endo- and exogenous signals, including toxins, redox potential, and light. The activity of these proteins as transcription factors depends on nucleocytoplasmic shuttling: the signal received in the cytoplasm has to be transduced, via translocation, to the nucleus. It leads to the activation of transcription of particular genes and determines the cell response to different stimuli. In this review, we aim to present the current state of knowledge concerning signals that affect shuttling of bHLH-PAS transcription factors. We summarize experimentally verified and published nuclear localization signals/nuclear export signals (NLSs/NESs) in the context of performed in silico predictions. We have used most of the available NLS/NES predictors. Importantly, all our results confirm the existence of a complex system responsible for protein localization regulation that involves many localization signals, which activity has to be precisely controlled. We conclude that the current stage of knowledge in this area is still not complete and for most of bHLH-PAS proteins an experimental verification of the activity of further NLS/NES is needed.

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“…Overall, the positive and negative feedback loops are orchestrated to repeat in a continuous 24 h rhythm, which forms the basis of the circadian periodicity [15,16,17]. In the translational segment of CC (not shown in Figure 1), the cytosolic BMAL1 protein stimulates translation upon phosphorylation by ribosomal S6 protein kinase, which increases its interaction with the translation machinery [10,11]. In addition, light-induced entrainment of the master CC in the SCN of the hypothalamus is promoted by phosphorylation of the translation initiation factor eIF4E, which specifically stimulates translation of Per mRNAs [18].…”

Section: The Mammalian Circadian Clockmentioning

confidence: 99%

“…This is a simplified snapshot of the highly complex circadian clock (CC) [2,3,4,5,6,7,8,9], depicting only the core pathways and the central players in transcriptional control. Most of the translational steps, including translation regulation by BMAL1 [10,11], are not shown for simplicity, but some are mentioned in the text of Section 2. As shown here and detailed in Section 2, the mammalian cell-autonomous 24-h CC is regulated by the core transcriptional activators (BMAL1, CLOCK) and two families of repressors (PER1, PER2 and CRY1, CRY2).…”

Section: Figurementioning

confidence: 99%

Molecular Interactions between Pathogens and the Circadian Clock

Barik

2019

IJMS

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The daily periodicity of the Earth’s rotation around the Sun, referred to as circadian (Latin “circa” = about, and “diem” = day), is also mirrored in the behavior and metabolism of living beings. The discovery that dedicated cellular genes control various aspects of this periodicity has led to studies of the molecular mechanism of the circadian response at the cellular level. It is now established that the circadian genes impact on a large network of hormonal, metabolic, and immunological pathways, affecting multiple aspects of biology. Recent studies have extended the role of the circadian system to the regulation of infection, host–pathogen interaction, and the resultant disease outcome. This critical review summarizes our current knowledge of circadian-pathogen interaction at both systemic and cellular levels, but with emphasis on the molecular aspects of the regulation. Wherever applicable, the potential of a direct interaction between circadian factors and pathogenic macromolecules is also explored. Finally, this review offers new directions and guidelines for future research in this area, which should facilitate progress.

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Cytosolic BMAL1 moonlights as a translation factor

Cited by 8 publications

References 10 publications

Quantitative live imaging of Venus::BMAL1 in a mouse model reveals complex dynamics of the master circadian clock regulator

Quantitative live imaging of Venus::BMAL1 in a mouse model reveals complex dynamics of the master circadian clock regulator

Subcellular Localization Signals of bHLH-PAS Proteins: Their Significance, Current State of Knowledge and Future Perspectives

Molecular Interactions between Pathogens and the Circadian Clock

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