The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases

Zhu, Shengyu; Yao, Ren-qi; Li, Yuxuan; Zhao, Peng-yue; Du, Xiaohui; Yao, Yong-ming

doi:10.3389/fcell.2021.667750

Cited by 30 publications

(28 citation statements)

References 145 publications

(195 reference statements)

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Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

“…The activation of TFEB is mainly regulated by posttranslational mechanisms (Zhu et al, 2021) (Figure 1). The mechanistic target of rapamycin complex 1 (mTORC1) and calcineurin are two central modulators that function in an opposing manner to connect upstream pathways with the phosphorylation of TFEB and its cytoplasmic/nuclear distribution (Zhu et al, 2021). Activated mTORC1 phosphorylates the Ser/Thr residue (S211) of TFEB; this allows binding to the YWHA/14-three to three protein that restricts TFEB from nuclear translocation (Irazoqui, 2020).…”

Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

“…Subsequently, TFEB upregulates the CLEAR gene network and enhances autophagy and the biogenesis of lysosomes (Irazoqui, 2020). TFEB can also be directly dephosphorylated by protein kinase B (Akt) (S467), glycogen synthase kinase 3β (GSK3β) (S138), and extracellular regulated protein kinase 2 (ERK2) (S142), thus suggesting a complicated regulatory pattern of phosphorylation/dephosphorylation that balances the activation of TFEB (Zhu et al, 2021). In addition to phosphorylation, epigenetic mechanisms may also modulate the activity of TFEB (Zhu et al, 2021).…”

Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

“…TFEB can also be directly dephosphorylated by protein kinase B (Akt) (S467), glycogen synthase kinase 3β (GSK3β) (S138), and extracellular regulated protein kinase 2 (ERK2) (S142), thus suggesting a complicated regulatory pattern of phosphorylation/dephosphorylation that balances the activation of TFEB (Zhu et al, 2021). In addition to phosphorylation, epigenetic mechanisms may also modulate the activity of TFEB (Zhu et al, 2021). For example, the deacetylation of TFEB enhances its activation in microglia cells (Bao et al, 2016) while ubiquitination degrades phosphorylated TFEB and subsequently enhances activity of the ALP (Sha et al, 2017).…”

Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

“…TFEB is an important pharmacological target in neurodegenerative, metabolic and malignant diseases, which was comprehensively summarized by previous literatures (Martini-Stoica et al, 2016;Raben and Puertollano, 2016). Meanwhile, recent studies have increasingly focused on its putative roles in immune modulation and organ protection, thereby implicating a close relationship with the development and outcomes of sepsis (Irazoqui, 2020;Zhu et al, 2021) (Figure 1).…”

Section: Tfeb and Tfeb Dependent Alp In Sepsismentioning

confidence: 99%

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TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

Liu

Zheng

et al. 2021

Front. Pharmacol.

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Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis.

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Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

Section: Tfeb Is a Central Regulatory Hub Of The Alpmentioning

confidence: 99%

Section: Tfeb and Tfeb Dependent Alp In Sepsismentioning

confidence: 99%

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TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

Liu

Zheng

et al. 2021

Front. Pharmacol.

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(S)‐ML‐SA1 Activates Autophagy via TRPML1‐TFEB Pathway

Cunha,

Do Amaral,

Takarada

et al. 2024

ChemBioChem

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Autophagic flux plays a crucial role in various diseases. Recently, the lysosomal ion channel TRPML1 has emerged as a promising target in lysosomal storage diseases, such as mucolipidosis. The discovery of mucolipin synthetic agonist‐1 (ML‐SA1) has expanded our understanding of TRPML1's function and its potential therapeutic uses. However, ML‐SA1 is a racemate with limited cellular potency and poor water solubility. In this study, we synthetized rac‐ML‐SA1, separated the enantiomers by chiral liquid chromatography and determined their absolute configuration by vibrational circular dichroism (VCD). In addition, we focused on investigating the impact of each enantiomer of ML‐SA1 on the TRPML1‐TFEB axis. Our findings revealed that (S)‐ML‐SA1 acts as an agonist for TRPML1 at the lysosomal membrane. This activation prompts transcription factor EB (TFEB) to translocate from the cytosol to the nucleus in a dose‐dependent manner within live cells. Consequently, this signaling pathway enhances the expression of coordinated lysosomal expression and regulation (CLEAR) genes and activates autophagic flux. Our study presents evidence for the potential use of (S)‐ML‐SA1 in the development of new therapies for lysosomal storage diseases that target TRPML1.

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The dual and emerging role of physical exercise‐induced TFEB activation in the protection against Alzheimer's disease

Morais

Neto

Marafon

et al. 2023

Journal Cellular Physiology

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The mechanisms of autophagy have been related to Alzheimer's disease (AD) pathogenesis by the endosomal‐lysosomal system, having a critical function in forming amyloid‐β (Aβ) plaques. Nevertheless, the exact mechanisms mediating disease pathogenesis remain unclear. The transcription factor EB (TFEB), a primary transcriptional autophagy regulator, improves gene expression, mediating lysosome function, autophagic flux, and autophagosome biogenesis. In this review, we present for the first time the hypothesis of how TFEB, autophagy, and mitochondrial function are interconnected in AD, providing a logical foundation for unraveling the critical role of chronic physical exercise in this process. Aerobic exercise training promotes Adiponectin Receptor 1 (AdipoR1)/AMP‐activated protein kinase (AMPK)/TFEB axis activation in the brain of the AD animal model, which contributes to alleviated Aβ deposition and neuronal apoptosis while improving cognitive function. Moreover, TFEB upregulates Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) and nuclear factor erythroid 2‐related factor 2 (NRF‐2), improving mitochondrial biogenesis and redox status. In addition, tissue contraction activates calcineurin in skeletal muscle, which induces TFEB nuclear translocation, raising the hypothesis that the same would occur in the brain. Thus, a deep and comprehensive exploration of the TFEB could provide new directions and strategies for preventing AD. We conclude that chronic exercise can be an effective TFEB activator, inducing autophagy and mitochondrial biogenesis, representing a potential nonpharmacological strategy contributing to brain health.

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The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases

Cited by 30 publications

References 145 publications

TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

(S)‐ML‐SA1 Activates Autophagy via TRPML1‐TFEB Pathway

The dual and emerging role of physical exercise‐induced TFEB activation in the protection against Alzheimer's disease

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