Aug 06, 2020 overexpressing mir30b5p in mice livers showed a decrease in lysosomal biogenesis and autophagy. Frontiers tfeb gene promoter variants effect on gene. This effector pathway was sufficiently important that inhibition of tfeb or lysosomes unveiled a striking harmful effect of excess pgc1. Emerging role of transcription factor eb in mitochondrial quality. 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. 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. Tfeb regulates pluripotency transcriptional network in mouse. Nearly all receptors serving lysosome biogenesis are under the transcriptional control of transcription factor eb tfeb, a master regulator of the lysosomal system. Using r 3000 kgm 3, which is a common choice in other. Jan 24, 2019 tfeb links autophagy to lysosomal biogenesis. Transcription factor eb tfebmediated autophagy protects. Finally, we assessed the role of gcn5 in lysosomal biogenesis in drosophila. Using lcms, we show accumulation of meki in the lysosomes of treated cells.
Oct 05, 2020 tfeb, a master regulator of lysosomal biogenesis, controls expression of a range of autophagy genes. 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. These in vitro and in vivo data indicate that mir30b5p may inhibit the tfeb dependent. Carmine settembre tfeb links autophagy to lysosomal biogenesis this copy is for your personal, noncommercial use only. Instead rna sequencing identified coordinated regulation of lysosomal biogenesis via tfeb. Tfeb links autophagy to lysosomal biogenesis ncbi nih. In response to stress tfe3 regulates not only autophagic and lysosomal genes, but. Pdf tfeb links autophagy to lysosomal biogenesis semantic. The transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and.
Therefore, by modulating the processes of lysosomal biogenesis, autophagy and. The tumor suppressor p53 regulates autophagosomal and. The liver specific loss and gain of functional studies revealed a crucial role of tfeb in lipid metabolism. Tfeb, a master regulator of lysosome biogenesis and.
Jci insight tfebdriven lysosomal biogenesis is pivotal. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. Feb 01, 2019 tfeb links autophagy to lysosomal biogenesis. Pomegranate activates tfeb to promote autophagylysosomal. Calcium is a universal second messenger that plays fundamental roles in cellular physiology. Tfeb coordinates the expression of lysosomal hydrolases, lysosomal membrane proteins, and autophagy proteins in response to pathways sensing lysosomal stress and the nutritional. Transcription factor eb tfeb is a master regulator of autophagy and lysosomal biogenesis. Trpml1 links lysosomal calcium to autophagosome biogenesis. The phytoestrogen genistein modulates lysosomal metabolism and. Yy1 cooperates with tfeb to regulate autophagy and lysosomal.
Tfeb links autophagy to lysosomal biogenesis request pdf. The activation of tfeb is enhanced by translocation to nucleus while decreasing tfeb level in the cytoplasm 23. Impaired tfebmediated lysosome biogenesis and autophagy. Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response. Since tfeb regulates processes like lysosomal biogenesis, autophagy and lysosomal exocytosis, therefore, it is able to modulate various cellular degradative pathways. Altered tfebmediated lysosomal biogenesis in gaucher. Transcription factoreb tfeb is emerging as a master gene for 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. The autophagy lysosomal pathway alp is involved in the degradation of longlived proteins. Though autophagy has been implicated in several human diseases, little is known regarding tfeb gene expression and regulation in the process. Oct 28, 2015 tfeb increases lysosomal biogenesis following cccp. Tfeb transcription factor eb is a master regulator of lysosomal pathways, governing lysosomal biogenesis and metabolism 17, autophagy 18, and lysosomal exocytosis 19 and a c c e p t e d m. The subcellular localization and activity of tfeb are regulated by mechanistic target of rapamycin mtormediated phosphorylation, which occurs at the lysosomal surface. Deficits in the alp result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of alzheimers disease ad, parkinsons disease pd, huntingtons disease hd, and prion disease.
The autophagylysosomal pathway in neurodegeneration. Tfeb also promotes lysosomal exocytosis for the cellular clearance. Tfebmediated lysosomal biogenesis and lysosomal drug. Tfeb has been demonstrated as a crucial regulator of lysosomal biogenesis and.
During starvation, the cell expands both compartments to enhance degradation processes. Tfeb links autophagy to lysosomal biogenesis carmine settembre, 1,2,3 chiara di malta, 1 vinicia assunta polito, moises garcia arencibia, 4 francesco vetrini, 2 serkan. Feb 15, 2019 the transcription factor eb tfeb is a master regulator for lysosomal biogenesis by enhancing expression of autophagy and lysosomal related genes. Settembre c, di malta c, polito va, garcia arencibia m, vetrini f, erdin s, et al. The expression of autophagy and lysosomal genes is coordinated by the transcription factor eb tfeb. The autophagylysosomal pathway alp is involved in the degradation of longlived proteins. 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. The transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Tfeb and tfe3 are novel components of the integrated stress. The transcription factor eb tfeb plays a pivotal role in the regulation of basic cellular processes, such as lysosomal 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. Tfeb, a master regulator of lysosome biogenesis and autophagy, is. Transcription factor eb agonists from natural products for treating.
Tfeb transcription factor eb homo sapiens human tfeb. Jci insight tfebdriven lysosomal biogenesis is pivotal for. Source data for figure 1 embr201948335sup0003sdatafig1. Endothelial tfeb transcription factor eb positively regulates. Emerging role of transcription factor eb in mitochondrial. Tfeb protects nucleus pulposus cells against apoptosis and. Tfeb is master regulator of clear gene network consisting of over 400 genes, which encoded proteins for lysosomal biogenesis and function. Tfeb and the clear network regulate lysosomal biogenesis. Tfeb links autophagy to lysosomal biogenesis nasaads. Increase in lysosomal content was associated with nuclear translocation of the transcription factor eb tfeb and upregulation of tfeb target genes. The transcription factor eb regulates the expression of clear motifcontaining target genes involved in autophagy and lysosomal biogenesis.
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. Source data for figure 1 embj201593428sup0002sdatafig1. The importance of tfeb in lysosomal function and neuronal survival is underlined by reports that in many neurodegenerative disease models, enhancement of tfeb function. Impaired tfebmediated lysosomal biogenesis promotes the. Trehalose induces macrophage autophagylysosomal biogenesis. Mittfe transcription factors tfs are master regulators of lysosomal and melanosomal biogenesis and autophagy and their activity is inhibited by mtorc1 89.
We also observed tfeb mediated regulation of lamp1 protein and gene expression of map1lc3 and vps11. Pdf the transcription factor tfeb links mtorc1 signaling to. The nuclear translocation of a transcription factor that promotes lysosomal biogenesis is inhibited when lysosomal function is adequate. We investigated the role and mechanisms of tfeb transcription factor eb, a master regulat. A highresolution version of the poster and individual poster panels are available for downloading at. However, the transcriptional control governing the autophagy lysosomal process in pancreatitis is largely unknown. Tfeb controls cellular lipid metabolism through a starvationinduced autoregulatory loop.
Acetyltransferase gcn5 regulates autophagy and lysosome. Aug 01, 2020 these opposite results of tfeb deletion may be due to the compensatory by tfe3, which also binds to clear elements and induces upregulation of multiple genes involved in lysosomal biogenesis and autophagy. Induction of lysosomal biogenesis in atherosclerotic. 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. The awesome lysosome embo molecular medicine embo press. Autophagy is activated by a broad range of cellular stress. Transcription factor eb tfeb is the master activator that regulates the transcription of genes involved in autophagy and lysosomal biogenesis. Lysosomal biogenesis requires the transcription factor tfeb, and roczniakferguson et al. Critical role of tfebmediated lysosomal biogenesis in. 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.
Pdf tfeb links autophagy to lysosomal biogenesis serkan. Regulation of tfeb activity and its potential as a therapeutic target. Tfeb links autophagy to lysosomal biogenesis carmine settembre,1,23 chiara di malta,1 vinicia assunta polito,1,2,3 mo. Nuclear mir30b5p suppresses tfebmediated lysosomal.
Transcription factor eb tfeb, a wellknown master regulator of autophagy and lysosomal biogenesis, is a member of the microphthalmia. We found that starvation activates a transcriptional program that controls major steps of the autophagic. E4 promotes autophagy flux and lysosomal biogenesis, reduces. Tfeb has been identified as a master regulator of lysosomal biogenesis and function that directly binds to clear. Tfeb transcription factor eb is the master regulator governing gene regula tion of autophagy and lysosomal biogenesis. 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. Impaired macroautophagy autophagy has been implicated in experimental and human pancreatitis. Rrag gtpases link nutrient availability to gene expression. 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. Autophagy is involved in many physiological processes.
Overexpression of tfeb induced autophagosome formation and autophagy lysosomal biogenesis. Our results suggest that gba1 mutations interfere with tfeb mediated lysosomal biogenesis, and that the action of gcase in maintaining a functioning pool of. Transcription factor eb tfeb is a master regulator of autophagy and coordinates the expression of autophagic proteins, lysosomal hydrolases, and lysosomal membrane proteins. Cardiovascular diseases cvds are the leading cause of death and a major cause of disability globally. Tfebdriven lysosomal biogenesis is pivotal for pgc1. Exploiting macrophage autophagylysosomal biogenesis as a. These are important part of autophagic machinery 10. Transcription factor eb regulates cardiovascular homeostasis. Tfeb links autophagy to lysosomal biogenesis autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes.
One of the genes that tfeb regulates is gba1, which encodes for the lysosomal enzyme gcase ec 3. Tfeb, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease. Jul 28, 2017 tfeb transcription factor eb is a master regulator for transcription of genes involved in autophagy and lysosomal biogenesis sardiello et al, 2009. Sensing lysosomal status lysosomes clear cells of damaged organelles, cellular debris, and internalized materials. Tfeb links autophagy to lysosomal biogenesis science. Endothelial tfeb transcription factor eb positively. Tfebmtorc1 feedback loop in metabolism and cancer cell stress. The transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinates this program by driving expression of autophagy and. Emerging studies suggest that tfeb regulates homeostasis in the cardiovascular system and shows. Altered tfebmediated lysosomal biogenesis in gaucher disease. Jun 01, 20 phosphorylation in s211 promotes interaction of tfeb with the cytosolic chaperone ywha 1433 and consequent retention of tfeb in the cytosol. By augmenting macrophage tfeb, the master transcriptional regulator of autophagylysosomal biogenesis, we can reverse the autophagy. Activity of tfeb is inhibited upon its serine phosphorylation by the mammalian target of rapamycin mtor. 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.
Tfeb, a master regulator of lysosomal biogenesis, controls expression of a range of autophagy genes. Request pdf tfeb links autophagy to lysosomal biogenesis autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Tfeb, a master regulator of lysosome biogenesis and autophagy. Mitochondrial and lysosomal biogenesis are activated. In addition to regulating the transcription of p62, tfeb has been reported to be a master regulator of lysosomal biogenesis sardiello et al. The transcription factor eb tfeb plays a pivotal role in the regulation of basic. Table 3selected genes with a known role in lysosomal biogenesis andor function, also encoding enzymes of. Pdf altered tfebmediated lysosomal biogenesis in gaucher. However, the cotranscriptional factors of tfeb are rarely identified. Yy1 cooperates with tfeb to regulate autophagy and.
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