Recent studies have shown that tfeb is a major transcription regulator of autophagy lysosomal pathway alp transcriptional regulation, which positively regulates the expression of autophagy and lysosomal biogenesis related genes, thereby promoting autophagosome formation, autophagosomelysosome fusion, and degradation of autophagy substrates. Tfeb, a master regulator of lysosome biogenesis and. Pdf the transcription factor tfeb links mtorc1 signaling. Impaired tfebmediated lysosomal biogenesis promotes the. Several studies have also found that tfeb protects cells from oxidative stress via autophagy either in vitro or in vivo 69, 81, 82, 83. Tfeb regulates pluripotency transcriptional network in mouse. E4 promotes autophagy flux and lysosomal biogenesis, reduces. Nuclear localization and activity of tfeb were regulated by serine phosphorylation mediated by the extracellular signalregulated kinase 2, whose activity was tuned by the levels of. Jun 15, 2018 subsequent studies have shown that tfeb is also a key transcriptional regulator of autophagy biogenesis, in addition to its crucial role in lysosomal function 32, 61. A functional endosomal pathway is necessary for lysosome. The liver specific loss and gain of functional studies revealed a crucial role of tfeb in lipid metabolism. Instead rna sequencing identified coordinated regulation of lysosomal biogenesis via tfeb. Finally, we examined the format of the cell death via detection of one apoptotic marker.
Tfeb controls cellular lipid metabolism through a starvationinduced autoregulatory loop. These results provide compelling evidence for a regulatory link between accumulation of protein aggregates and tfeb mediated impaired lysosomal biogenesis and autophagy in the placenta of pe patients. Transcription factor eb tfeb, also known as bhlhe35 or alphatfeb, a member of the microphthalmia family mitftfe family, is a master transcriptional regulator of lysosomal biogenesis and autophagy and regulates the expression of various lysosome and autophagy genes. Tfeb links autophagy to lysosomal biogenesis carmine settembre,1,23 chiara di malta,1 vinicia assunta polito,1,2,3 mo. Request pdf tfeb links autophagy to lysosomal biogenesis autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes.
Tfeb also promotes lysosomal exocytosis for the cellular clearance. Porcine hemagglutinating encephalomyelitis virus induces. The transcription factor eb tfeb plays a pivotal role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy. Jci insight tfebdriven lysosomal biogenesis is pivotal. Herein, tfeb, as a master regulator of autophagy and lysosomal biogenesis, is a potential molecular target to enhance or restore the capacity of cellular clearance and to protect cells against pathological conditions. We found that the mechanism of arsenitestimulated tfeb and tfe3. Since tfeb regulates processes like lysosomal biogenesis, autophagy and lysosomal exocytosis, therefore, it is able to modulate various cellular degradative pathways.
Activity of tfeb is inhibited upon its serine phosphorylation by the mammalian target of rapamycin mtor. Therefore, by modulating the processes of lysosomal biogenesis, autophagy and. Cathepsin b modulates lysosomal biogenesis and host defense. Lysosomotropic drugs activate tfeb via lysosomal membrane. During starvation, the cell expands both compartments to enhance degradation processes. Cathepsin b modulates lysosomal biogenesis and host. The recently discovered transcription factor eb tfeb is the only known transcription factor that drives the expression of a majority of lysosomal and autophagy genes. Tfeb, a master regulator of lysosome biogenesis and autophagy, is. Tfeb links autophagy to lysosomal biogenesis request pdf. Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. However, the biological role and clinical significance of tfeb in prostate cancer pca remain unknown. Tfeb links autophagy to lysosomal biogenesis carmine settembre et al. Phosphorylated tfeb is retained in the cytoplasm, whereas dephosphorylated.
Subsequent experiments showed that the transcription factor eb tfeb positively regulates the expression of lysosomal genes and acts as a master regulator of lysosomal biogenesis sardiello et al. Here, we initially aimed to investigate the links between p38 map kinase and tfeb tfe3mediated autophagy and lysosomal biogenesis. We found that starvation activates a transcriptional program that controls major steps of the autophagic p. Regulation of tfeb activity and its potential as a therapeutic target. The transcription factor eb tfeb is a major regulator of lysosomal biosynthesis, which is coordinated by driving autophagy and expression of lysosomal genes settembre et al. Tfeb, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease. Yy1 cooperates with tfeb to regulate autophagy and. Transcription factor eb tfeb, as a member of the microphthalmia transcription factor mitf family, has been demonstrated to be a master regulator of autophagy and lysosomal biogenesis. Tfeb activity is inhibited following its phosphorylation by mammalian target of rapamycin complex 1 mtorc1 on the surface of the lysosome. Here, we initially aimed to investigate the links between p38 map kinase and tfebtfe3mediated autophagy and lysosomal biogenesis. We also observed tfeb mediated regulation of lamp1 protein and gene expression of map1lc3 and vps11. Tfeb links autophagy to lysosomal biogenesis autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Tfeb links autophagy to lysosomal biogenesis carmine settembre, 1,2,3chiara di malta,1 vinicia assunta polito, moises garcia arencibia,4 francesco vetrini,2 serkan erdin, 2,3serpil uckac erdin, tuong huynh,2,3 diego medina,1 pasqualina colella,1 marco sardiello,2,3 david c. Tfeb links autophagy to lysosomal biogenesis science.
If you wish to distribute this article to others, you can order highquality copies for your colleagues, clients, or customers by clicking here. Mar 14, 2019 termed the coordinated lysosomal expression and regulation network clear network, tfeb s gene targets link early steps of autophagy to lysosomal biogenesis to drive an integrated program for cellular waste removal 40, 41. The expression of autophagy and lysosomal genes is coordinated by the transcription factor eb tfeb. Jci insight tfebdriven lysosomal biogenesis is pivotal for.
Jun 01, 20 phosphorylation in s211 promotes interaction of tfeb with the cytosolic chaperone ywha 1433 and consequent retention of tfeb in the cytosol. The restoration of autophagy and lysosomal function becomes a promising strategy to treat these diseases. Using a chronic plus acute alcohol binge referred to as gaobinge mouse model, we analyzed pancreas injury, autophagic flux, zymogen granule removal, tfeb nuclear translocation and lysosomal biogenesis in gfplc3 transgenic mice, acinar cellspecific atg5 knockout ko and tfeb ko mice as well as their matched wild type mice. Tfeb regulates pluripotency transcriptional network in. Transcription factor eb tfeb, a member of the mit family, is dysregulated in different cancers and exerts specific biological functions within the tumor microenvironment. Transcription factor eb regulates cardiovascular homeostasis. Pdf tfeb links autophagy to lysosomal biogenesis serkan. Abstract autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Pdf tfeb links autophagy to lysosomal biogenesis diego. Induction of lysosomal biogenesis in atherosclerotic. Cathepsin b can also mediate trypsinogen activation to promote the development of acute pancreatitis van acker et al. Among other regulators of lysosome function, transcription factor eb tfeb stands out the most as it regulates both lysosome biogenesis and functions such as autophagy, lysosomal exocytosis, macromolecule degradation and mtor signaling 2 figure 1.
Figure 1 various roles of transcription factor eb tfeb in cellular processes. Cdk46 interact with and phosphorylate tfebtfe3 in the nucleus, thereby inactivating them. Evidence for lysosomal biogenesis proteome defect and. Nuclear localization and activity of tfeb were regulated by serine phosphorylation mediated by the extracellular signalregulated kinase 2, whose activity was tuned by the levels of extracellular nutrients.
Critical role of tfebmediated lysosomal biogenesis in. Frontiers tfeb promotes prostate cancer progression via. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. A stress response p38 map kinase inhibitor sb202190 promoted. Transcription factor eb tfeb, a wellknown master regulator of autophagy and lysosomal biogenesis, is a member of the microphthalmia. Pomegranate activates tfeb to promote autophagylysosomal. Transcription factor eb tfeb, a wellknown master regulator of autophagy and lysosomal biogenesis, is a member of the microphthalmia family of transcription factors mit family. Cdk46 regulate lysosome biogenesis through tfebtfe3 journal.
Yy1 cooperates with tfeb to regulate autophagy and lysosomal. Tfeb mediated lysosomal biogenesis and autophagy are crucial in exogenous antigen presentation and cancer metabolism perera et al. Cardiovascular diseases cvds are the leading cause of death and a major cause of disability globally. Emerging role of transcription factor eb in mitochondrial.
The importance of tfeb in lysosomal function and neuronal survival is underlined by reports that in many neurodegenerative disease models, enhancement of tfeb function. This regulation is exerted through tfeb binding to the clear coordinated lysosomal expression and regulation element in the promoters of autophagy and lysosomal genes 25, 26. Tfeb links autophagy to lysosomal biogenesis pubmed nih. Therefore, tfeb provides coordinated transcriptional regulation of the two main degradative organelles in the cell, autophagosomes and lysosomes. Cdk46 regulate lysosome biogenesis through tfebtfe3. This effector pathway was sufficiently important that inhibition of tfeb or lysosomes unveiled a striking harmful effect of excess pgc1. Tfeb regulates lysosomal proteostasis human molecular. Emerging roles and regulation of mittfe transcriptional. Lysosomal biogenesis requires the transcription factor tfeb, and roczniakferguson et al. Tfeb transcription factor eb is a master regulator for transcription of genes involved in autophagy and lysosomal biogenesis sardiello et al, 2009. Altered tfebmediated lysosomal biogenesis in gaucher disease. May 26, 2011 tfeb links autophagy to lysosomal biogenesis carmine settembre, 1, 2, 3 chiara di malta, 1 vinicia assunta polito, 1, 2, 3 moises garcia arencibia, 4 francesco vetrini, 2 serkan erdin, 2, 3 serpil uckac erdin, 2, 3 tuong huynh, 2, 3 diego medina, 1 pasqualina colella, 1 marco sardiello, 2, 3 david c. Transcription factor eb agonists from natural products for treating. Tfeb links autophagy to lysosomal biogenesis ncbi nih.
Endothelial tfeb transcription factor eb positively. On the other hand, lysosomal biogenesis also requires the integration of the endosomal and biosynthetic. The important role of tfeb in autophagylysosomal pathway and. A critical question for understanding tfeb regulation is how cells link tfeb rrag gtpases link nutrient availability to gene expression, autophagy and lysosomal biogenesis. Altered tfebmediated lysosomal biogenesis in gaucher. Pdf tfeb links autophagy to lysosomal biogenesis semantic. These are important part of autophagic machinery 10. Lysosomal biogenesis is orchestrated by the transcription factor eb tfeb which activates the transcription of 500 target genes involved in lysosomal biogenesis and autophagy 2, 3. Transcription factor eb tfeb is a master transcriptional regulator playing a key role in lysosomal biogenesis, autophagy and lysosomal exocytosis. Cell survival relies on the ability to adapt to different extracellular environments. Pdf the transcription factor tfeb links mtorc1 signaling to. Emerging studies suggest that tfeb regulates homeostasis in the cardiovascular system and shows. For example, during nutrient deprivation the cell decreases anabolic activity and enhances intracellular catabolism in the attempt to preserve and generate energy. We investigated the role and mechanisms of tfeb transcription factor eb, a master regulat.
Sensing lysosomal status lysosomes clear cells of damaged organelles, cellular debris, and internalized materials. These genes are known to positively regulating genes belonging to the co inhibitor e64, which are lysosomal inhibitors of play a role in different steps of autophagy fig. Authors carmine settembre 1, chiara di malta, vinicia assunta polito, moises garcia arencibia, francesco vetrini, serkan erdin, serpil uckac erdin, tuong huynh, diego medina, pasqualina colella, marco sardiello. The important role of tfeb in autophagylysosomal pathway. Protein phosphatase 2a stimulates activation of tfeb and tfe3. The transcription factor eb tfeb plays a pivotal role in the regulation of. Tfeb, a master regulator of lysosomal biogenesis, controls expression of a range of autophagy genes. Here, our findings define a mechanism that regulates lysosome biogenesis during the cell cycle. Transcription factor eb tfeb is the master activator that regulates the transcription of genes involved in autophagy and lysosomal biogenesis. The transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. These results identify tfeb as a target of mtor and suggest a mechanism for matching the transcriptional regulation of genes encoding proteins of autophagosomes and lysosomes to cellular need.
Accumulating evidence has highlighted tfeb as a regulator of mitochondrial homeostasis in part by. The transcription factor tfeb links mtorc1 signaling to. Downregulation of tfeb induces macrophage polarization in the tme and promotes tumor progression. Tfeb transcription factor eb was recently discovered as a master regulator of alp due to its ability to coordinate expression of autophagy and lysosomal target genes and enhance lysosomal. The nuclear translocation of a transcription factor that promotes lysosomal biogenesis is inhibited when lysosomal function is adequate. Apr 18, 20 it has been shown that overexpression of tfeb, a master regulator of lysosomal biogenesis and autophagy, leads to the generation of new lysosomes and increased numbers of autophagosomes in a variety of cell types sardiello et al, 2009. Find, read and cite all the research you need on researchgate. Tfeb, a master regulator of lysosome biogenesis and autophagy. Upon inactivation of mtorc1 by starvation, the tfeb ywha complex dissociates and tfeb is free to enter the nucleus and activate lysosomal biogenesis and autophagy. The subcellular localization and activity of tfeb are regulated by mechanistic target of rapamycin mtormediated phosphorylation, which occurs at the lysosomal surface. Jan 24, 2019 transcription factor eb tfeb is a master regulator of autophagy and lysosomal genes. We found that starvation activates a transcriptional program that controls major steps of the autophagic. Control of lysosomal biogenesis and notchdependent tissue.
The phosphorylated tfeb is the inactive form and is sequestered. Tfeb links autophagy to lysosomal biogenesis nasaads. Request pdf on jun 1, 2011, settembre c and others published tfeb links autophagy to lysosomal biogenesis. In cells with sufficient nutrients, pharmacological inhibition or genetic inactivation of cdk46 leads to nuclear retention and activation of tfeb and tfe3, consequently resulting in tfeb and tfe3dependent lysosome biogenesis and autophagy. Both gain and lossoffunction experiments have shown that tfeb regulates several aspects of lysosomal function.
Tfeb and 1433 proteins and the translocation of tfeb into the nucleus, where it could stimulate genes involved in lysosomal biogenesis. Rrag gtpases link nutrient availability to gene expression. Jun 17, 2011 the transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Aug 01, 2020 tfeb mediated autophagy could promote lysosomal biogenesis and function, regulate autophagic proteins, and thereby eliminate ros.
Transcription factor eb tfeb is a new therapeutic target. However, the transcriptional control governing the autophagy lysosomal process in pancreatitis is largely unknown. Impaired macroautophagy autophagy has been implicated in experimental and human pancreatitis. Curcumin targets the tfeblysosome pathway for induction of.
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