Tfeb, which drives molecular clearance, is a master regulator of lysosomal biogenesis and autophagy 20, 21. Transcriptional regulation of autophagylysosomal function in. Settembre c1, di malta c, polito va, garcia arencibia m, vetrini f, erdin s, erdin su, huynh t, medina d, colella p, sardiello m, rubinsztein dc, ballabio a. Lysosomal function may be influenced by mitochondrial quality control, dynamics andor respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, is not yet understood.
This repression is alleviated during nutrient deprivation through ampksirt1 signaling, allowing autophagy activation. Pdf tfeb links autophagy to lysosomal biogenesis diego. A gene network regulating lysosomal biogenesis and function marco sardiello, michela palmieri, alberto di ronza, diego luis medina, marta. Jun 25, 2009 a gene network regulating lysosomal biogenesis and function marco sardiello, michela palmieri, alberto di ronza, diego luis medina, marta valenza, vincenzo alessandro gennarino, chiara di malta, francesca donaudy, valerio embrione, roman s. As a master regulator of lysosome biogenesis, tfeb is known to promote cellular lysosomal capacity and autophagy.
Nutrient starvation, a physiological inducer of autophagy, promotes both autophagosome formation and lysosome biogenesis. Enhancement of liver autophagy increases degradation of mutant, hepatotoxic alpha1antitrypsin atz. Sublethal oxidative stress induces lysosome biogenesis. Transcriptional control of the autophagylysosome system. First, we asked whether macrophage autophagylysosome.
Tfeb an essential regulator of lysosome biogenesis. The lysosomal alterations described here are likely to be a major determinant in gba1associated neurodegeneration. What links here related changes upload file special pages permanent link page information wikidata item cite this. Relevant to this, mutations of proteins in autophagylysosome system. Pros and cons of different ways to address dysfunctional. Galectin3 coordinates a cellular system for lysosomal repair. Tfeb, a master regulator of lysosome biogenesis and autophagy. Tfeb regulates lysosomal positioning by modulating tmem55b. Our results suggest that gba1 mutations interfere with tfeb mediated lysosomal biogenesis, and that the action of gcase in maintaining a functioning pool of lysosomes is exerted in part through tfeb. Tmem55b contributes to lysosomal homeostasis and amino acid.
Altered tfebmediated lysosomal biogenesis in gaucher. According to this, in ncs34 cells treated with rotenone we found a decrease of lamp. Endocytosis is specifically needed for the degradation of membrane proteins whereas autophagy is responsible for the degradation of cytoplasmic. 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. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Recently, it was found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor eb tfeb, which also links autophagy to lysosome biogenesis 8, 9. Tfe3 fusions escape from controlling of mtor signaling. Under normal growth conditions tfeb is transiently recruited to the lysosomes through its interaction with active rag. We investigated the therapeutic potential of liverdirected gene transfer of transcription factor eb tfeb, a master gene that regulates lysosomal function and autophagy, in piz transgenic mice, recapitulating the human hepatic disease.
Loss of c9orf72 enhances autophagic activity via deregulated. The ampkskp2carm1 axis links nutrient sensing to transcriptional and epigenetic regulation of autophagy macroautophagyautophagy is a highly conserved catabolic process that targets bulk cytoplasm, and damaged organelles or other harmful intracellular content to. Tfeb, a master regulator of lysosome biogenesis and. Brd4 inhibition enhances autophagic flux and lysosomal function and. Autophagy, a process of lysosomal degradation essential for cellular homeostasis, is transcriptionally regulated by transcription factor eb tfeb, which coordinates the expression of genes involved in lysosome biogenesis, autophagy and endocytosis 1, 2, 4. Nucleustranslocated acss2 promotes gene transcription for. Silencing of zkscan3 augmented tfebmediated lysosomal and autophagic.
Autophagy is a fundamental catabolic process that plays a central role in health and disease. We have previously shown that tfeb, a master regulator of autophagy and lysosomal biogenesis 23, 24, can attenuate lipotoxic stress in macrophages, attenuate il1b secretion, and reduce atherosclerotic progression. Tfeb is the major transcription factor for lysosomal biogenesis and its cellular localization is counterregulated by. 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. Oct, 2017 the transcription factor eb tfeb is known to regulate expression of many genes involved in autophagy and lysosome biogenesis. Nov 16, 2016 lysosomes are the major catabolic compartment within eukaryotic cells, and their biogenesis requires the integration of the biosynthetic and endosomal pathways. Apr 12, 2019 braf v600e inhibitor triggers autophagylysosomal activation through tfeb. Ampk governs lineage specification through tfebdependent. Tfeb attenuates myocardial dysfunction after ir, improves lvef, and reduces il1. Pdf tfeb links autophagy to lysosomal biogenesis tuong. Zinc oxide particles induce activation of the lysosome. A recent study revealed that tfe3 can activate gene expression associated with autophagy and lysosomal biogenesis which promote cellular survival during starvation. The biogenesis of lysosomes and lysosomerelated organelles is discussed, taking into account their dynamic nature and multiple roles.
While il4 inhibits and activates different sets of lysosomal genes, stat6 mediates only the activating effects of il4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by il4. Oxidation of multiple mittfe transcription factors links oxidative. Rapamycin directly activates lysosomal mucolipin trp. Furthermore, it was demonstrated that lysosomal impairment can be due to mitochondrial ros production. Sublethal oxidative stress induces lysosome biogenesis via a.
The deubiquitinating enzyme ubpy is required for lysosomal. The transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Transfectants for fulllength tfeb and tfeb 3xflag were selected with 1 mgml g418 sigma. Jun 01, 2017 tfeb functions as a master gene in lysosomal biogenesis by coordinating expression of lysosomal hydrolases and membrane proteins and in expression of genes involved in autophagy sardiello et al. A functional endosomal pathway is necessary for lysosome biogenesis in drosophila anneclaire jacomin1,2,3,4, marieodile fauvarque1,2,3 and emmanuel taillebourg1,2,3 abstract background. All content in this area was uploaded by tuong tom huynh.
Autophagy activation by transcription factor eb tfeb in. A major player in the regulation of lysosomal biogenesis and function is the transcription factor eb tfeb. Jun 17, 2011 tfeb links autophagy to lysosomal biogenesis. Endocytosis and autophagy are the primary inputs of the lysosomal degradation pathway. Us provisional 61449751 070311 us provisional 61596485 080212 ferdinando gianfrancesco personal details name fernando gianfrancesco place and date of birth piedimonte matese ce, may 11 th, 1968 present position full researcher of the italian national research council cnr at institute of. Thus, increased lysosomal biogenesis accompanies the expanded autophagosome compartment in pda and may facilitate high levels of autophagic. A number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes. Nov 17, 2017 lysosomal distribution is linked to the role of lysosomes in many cellular functions. Tfeb functions as a master gene in lysosomal biogenesis by coordinating expression of lysosomal hydrolases and membrane proteins and in expression of genes involved in autophagy sardiello et al. Time course decomposition of cell heterogeneity in tfeb. By binding to motifs known as coordinated lysosomal expression and regulation clear elements found within the promoters of lysosomal genes tfeb is able to activate their transcription 1.
Lysosomal membrane proteomics and biogenesis of lysosomes. Depending on the specific physicochemical properties of the nanomaterial, however, nanoparticleinduced autophagy may have different effects on cell physiology, ranging from enhanced autophagic degradation to blockage of autophagic. Ferguson from yale university reported on the mechanisms whereby this transcription factor is regulated as part of a homeostatic feedback pathway that couples expression of autophagylysosomal genes to cellular demand. Upregulation of lysosomal trpml1 channels is essential for. Hepes activates a mittfedependent lysosomalautophagic gene. To reveal the involvement of p2x7 signaling in the process of lysosomal biogenesis, we measured the tfeb expression and its cellular localization after bzatp treatment. During starvation, the cell expands both compartments to enhance degradation processes. University of groningen lysosome biogenesis and autophagy. Apr 11, 2018 tfeb is thus phosphorylated by mtorc1 on lysosomes and is localized to the cytosol under nutrient. By augmenting macrophage tfeb, the master transcriptional regulator of autophagylysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62enriched protein aggregates and blunt macrophage apoptosis and proinflammatory il1. This file is now available in the html version of the article.
This article is distributed exclusively by cold spring harbor laboratory press for the first six months after the fullissue publication date see. Gene expression at the posttranscriptional level can be regulated by micrornas mirnas. Since tfeb regulates processes like lysosomal biogenesis, autophagy and lysosomal exocytosis, therefore, it is able to modulate various cellular degradative pathways. Transcriptional regulation of autophagylysosomal function. Transcription factor eb tfeb regulates lysosome biogenesis and autophagy. The transcription factor eb tfeb is known to regulate expression of many genes involved in autophagy and lysosome biogenesis. Depending on the specific physicochemical properties of the nanomaterial, however, nanoparticleinduced autophagy may have different effects on cell physiology, ranging from enhanced autophagic degradation to blockage of autophagic flux. For example, transcription factor tfeb, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mtor, a lysosomelocalized nutrient sensor.
Tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Gene transfer of master autophagy regulator tfeb results. Transcription factor eb tfeb is a new therapeutic target. A gene network regulating lysosomal biogenesis and function. To examine whether the potential correlation between tgf. Tmem55b contributes to lysosomal homeostasis and amino. Settembre c1, di malta c, polito va, garcia arencibia m, vetrini f, erdin s, erdin su, huynh t. Tfeb is thus phosphorylated by mtorc1 on lysosomes and is localized to the cytosol under nutrient. Jul 10, 2017 by augmenting macrophage tfeb, the master transcriptional regulator of autophagylysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62enriched protein aggregates and blunt macrophage apoptosis and proinflammatory il1. Tfeb represses myelination, and raga represses tfeb. This is a punctum to settembre c, di malta c, polito va, garcia arenchibia m, vetrini f, erdin s, et al, tfeb links autophagy to lysosomal biogenesis. Both lysosomal biogenesis and autophagy are specifically required for maintenance of intracellular amino acid pools perera et al. Our starting point to study lysosome biogenesis is to define the composition of the membrane by the use of proven methods for purification of lysosomes to near homogeneity and then to characterize membraneassociated and integral lysosomal membrane proteins.
Gene transfer of master autophagy regulator tfeb results in. These target genes include the autophagy genes uvrag, atg9b, map1lc3b, and sqstm1. Rnaseq data files are available in geo under accession number gse118463. Their substrates include all kinds of macromolecules delivered either by endocytosis, phagocytosis or autophagy. Exploiting macrophage autophagylysosomal biogenesis as a. Aspirin induces lysosomal biogenesis and attenuates amyloid plaque.
Notably, transcription of autophagy genes was reduced upon saha treatment in mefs dko for tfeb and tfe3 and silenced for mitf, suggesting. The ampkskp2carm1 axis links nutrient sensing to transcriptional and epigenetic regulation of autophagy macroautophagy autophagy is a highly conserved catabolic process that targets bulk cytoplasm, and damaged organelles or other harmful intracellular content to the lysosomevacuole for degradation. Transcriptional control of the autophagylysosome system in pancreatic cancer. Raw sequencing data were demultiplexed and converted into fastq files using casava version 1. Tfeb links autophagy to lysosomal biogenesis request pdf. Tfeb acts as a global controller of lysosomal biogenesis, autophagy, lysosomal. Tfeb, tfe3, and mitf, significantly blunted lysosome biogenesis and gene. Upregulation of lysosomal trpml1 channels is essential. Upon nutrient depletion and under aberrant lysosomal storage conditions such as in lysosomal storage diseases, tfeb. The lysosomal transcription factor tfeb represses myelination. Lysosomal distribution is linked to the role of lysosomes in many cellular functions. 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. In this study, we demonstrated that the overexpressed tfe3 fusions could promote the expression of lysosomal biogenesis genes.
Here the authors show that the lysosomal protein tmem55b is regulated by tfeb and recruits jip4 to the. The biogenesis of lysosomes and lysosomerelated organelles. Raw and processed data were returned and count files were. Braf v600e inhibitor triggers autophagylysosomal activation through tfeb.
Reducing mhtt levels through activation of the autophagosomelysosomal pathway may have therapeutic benefit. In addition, lysosomes are secretory organelles, with specialized machinery for regulated secretion of proteins in some cell types. Nuclear localization and activity of tfeb were regulated by serine phosphorylation mediated by the extracellular signalregulated kinase 2, whose activity was tuned by. We found that starvation activates a transcriptional. Organelle biogenesis and autophagy molecular biology of the. Request pdf on jun 1, 2011, settembre c and others published tfeb links autophagy to lysosomal biogenesis. Thus, galectins coordinate various stages of response to lysosomal damage and bridge escrt repair phase with autophagy and tfeb response figures 7g and s6f. Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Tfeb nuclear translocation, which increases as recently shown chauhan et al. 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. Request pdf tfeb links autophagy to lysosomal biogenesis autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Reprogramming of lysosomal gene expression by interleukin. Brd4 inhibition enhances autophagic flux and lysosomal function and promotes the degradation of protein aggregates.
Nov 23, 2015 a number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes. Tfeb links autophagy to lysosomal biogenesis science. Find, read and cite all the research you need on researchgate. In raga mutants, tfeb is hyperactive, and myelin is nearly eliminated.
Rapamycin directly activates lysosomal mucolipin trp channels. Polishchuk, sandro banfi, giancarlo parenti, elena cattaneo, andrea ballabio. Results showed a significant increase in the uptake of ao from 8h to 48h and ltr staining at 12h, 24h. Bromodomain protein brd4 is a transcriptional repressor of. Tfeb also promotes lysosomal exocytosis for the cellular clearance. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. Synergistic effect of mitochondrial and lysosomal dysfunction. Using genetic approaches in zebrafish, meireles and shen et al. Jci insight tfeb activation in macrophages attenuates. Apr 12, 20 recently, it was found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor eb tfeb, which also links autophagy to lysosome biogenesis 8, 9. Lysosomes are the major catabolic compartment within eukaryotic cells, and their biogenesis requires the integration of the biosynthetic and endosomal pathways. The current data establish stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Upon starvationinduced mtor inhibition, tfeb, a key regulator of autophagy and lysosome biogenesis, undergoes rapid activation via dephosphorylation and cytosoltonucleus translocation 1720.
Importantly, we observed a substantial increase of tfeb and its lysosomal targets in c9orf72 knockout mice. Tfeb, for example, is a known regulator of lysosome biogenesis. Organelle biogenesis and autophagy molecular biology of. Altered tfebmediated lysosomal biogenesis in gaucher disease.
Mcoln1 is a ros sensor in lysosomes that regulates autophagy. To examine if increasing tfeb protein levels in hd mouse striatum induces autophagy and influences mhtt levels. The liver specific loss and gain of functional studies revealed a crucial role of tfeb in lipid metabolism. Transcription factor eb is a protein that in humans is encoded by the tfeb gene function. Transcriptional control of the autophagylysosome system in. Lysosomal biogenesis is orchestrated by the transcription factor eb tfeb which activates the transcription of 500 target genes involved in. A functional endosomal pathway is necessary for lysosome. In addition to regulating the transcription of genes involved autophagosomallysosomal biogenesis, tfeb and tfe3 also facilitate lysosomal exocytosisa process of lysosomal fusion with plasma membrane leading to clearance of pathologically accumulated materials by discharging lysosomal content into the extracellular space. Tfe3 and tfeb are decoupled from regulatory mechanisms that.