Tfeb acts as a global controller of lysosomal biogenesis, autophagy. A stress response p38 map kinase inhibitor sb202190. The deubiquitinating enzyme ubpy is required for lysosomal. Amino acids direct mtorc1 to the surface of the late endosomelysosome, where mtorc1 becomes receptive to other inputs. Tfebmediated lysosomal biogenesis and autophagy are crucial in exogenous antigen presentation and cancer metabolism perera et al. Tfeb and tfe3 are master transcriptional regulators of autophagy and lysosome biogenesis in response to starvation. Lysosomal biogenesis given the clear lysosomal activation demonstrated by increased lysosomal volume and cathepsin activity, lysosomal biogenesis induced by the compound treatment was investigated. Tfeb represses myelination, and raga represses tfeb. Correspondingly, overexpression of tfeb has been shown to affect the expression of a unique set of genes that are related to lysosome function and. Trpml1 links lysosomal calcium to autophagosome biogenesis. Autophagy dysregulation in danon disease free download. 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.
The autophagic response to polystyrene nanoparticles is. Although tfe3 was not detected in either ms experiments figures 4 a and 4b, western blots show that tfe3 was also reduced by gc7 treatment in b cells figure s5 h. However, the characteristics of tfeb and its role in proteasome inhibition. Protein cell deacetylation of tfeb promotes fibrillar a. Rag gtpases mediate amino aciddependent recruitment of. The flag and lamp2 channels are in green and red, respectively, in the merge. To examine whether the potential correlation between tgf. Upregulation of lysosomal trpml1 channels is essential. The transcription factor eb tfeb plays a pivotal role in the regulation of basic. In this study, we found that cs induced tfeb nuclear localization and increased tfeb expression in.
Neo212 induces mitochondrial apoptosis and impairs. Gaucher disease gd is the most prevalent lsd and is caused by mutations in the gba1 gene, which encodes the lysosomal enzyme glucocerebrosidase gcase. Therefore, by modulating the processes of lysosomal biogenesis, autophagy. Tfeb has been shown to modulate lysosomal clearance by i regulating the expression of hydrolytic enzymes in the. Growing evidence indicates that proteasome inhibitioninduced alp activation is an adaptive response. These target genes include the autophagy genes uvrag, atg9b, map1lc3b, and sqstm1. Tfeb is a transcription factor that regulates both autophagy and lysosomal biogenesis via rapid translocation to the nucleus from the cytosol and lysosomes upon starvation 4, 12. Ubiquitinproteasome pathway ups and autophagylysosome pathway alp are the two major protein degradation pathways, which are critical for proteostasis. Tfeb links autophagy to lysosomal biogenesis article pdf available in science 3326036. In raga mutants, tfeb is hyperactive, and myelin is nearly eliminated. However, recent studies have revealed new roles for these transcription factors in the control of a number of diverse biological functions, including the inflammatory process, the unfolded protein response and metabolic regulation.
Tfeb transcription factor eb, which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for parkinsons disease pd. To date, the choice of anesthetics during surgery in. Cells free fulltext trehalose alleviates crystalline. Transcription factor eb tfeb is a master regulator of alp. The transcription factor tfeb links mtorc1 signaling to transcriptional control of lysosome. The transcription factor tfeb links mtorc1 signaling to transcriptional control of lysosome homeostasis. 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.
Tfeb, which drives molecular clearance, is a master regulator of lysosomal biogenesis and autophagy 20, 21. Using genetic approaches in zebrafish, meireles and shen et al. A group of basic helixloophelix leucine zipper transcription factors including tfeb, tfe3, and mitf have been shown to play critical roles in. Being a paralog of tfeb, tfe3 has also been reported to promote autophagy and lysosomal biogenesis martina et al. Tfeb probably involved in midazolamdisturbed lysosomal. 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. Tfeb, for example, is a known regulator of lysosome biogenesis. Gba1 mutation is also a known major risk factor for parkinsons. Nuclear localization and activity of tfeb were regulated by serine phosphorylation mediated by the extracellular. Lysosomal stress induces tfeb nuclear translocation. In the normal state, tfeb and tfe3 are predominantly localized in the cytoplasm.
It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. 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. To define the role of autophagy in human disease, we analyzed the muscle biopsies of dd patients and monitored autophagy and several autophagy regulators like transcription factor eb tfeb, a master player in lysosomal biogenesis, and vacuolar protein sorting 15 vps15, a critical factor for autophagosome and endosome biogenesis and trafficking. In this study, a curcumin derivative, named e4, was identified as a potent tfeb activator. Transcriptional control of the autophagylysosome system in pancreatic cancer the harvard community has made this. A functional endosomal pathway is necessary for lysosome.
Transcriptional control of the autophagylysosome system. Tfeb acts as a global controller of lysosomal biogenesis 2, autophagy 3, lysosomal exocytosis 4, lipid catabolism 5, energy metabolism 6, and. Tfeb expression markedly increased the levels of lysosomal membrane protein, preserved lysosomal protease activity, maintained the lysosomal. Upon starvation or lysosomal stress, inhibition of mtor and. 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. Frontiers proteasome inhibition activates autophagy. Ancient among the signals that regulate mtorc1 are nutrients. Interestingly, zkscan3 and tfeb are oppositely regulated by starvation and in turn oppositely regulate lysosomal biogenesis and autophagy, suggesting that they act in conjunction. Nucleustranslocated acss2 promotes gene transcription for. Tfeb is primed for activation in lysosomal storage disorders because of lysosomal stress, but tfeb function is impaired in some late. Altogether, our study uncovers an autophagy masterswitch regulating the expression of a transcriptional network of genes integral to autophagy and lysosome. Tfeb is a member of the basic helixloophelix leucine zipper family of transcription factors that controls lysosomal biogenesis and autophagy by positively regulating genes belonging to the clear coordinated lysosomal expression and regulation network sardiello and ballabio, 2009.
Lysosomal storage diseases lsds are a group of inherited metabolic disorders that are often characterized by neurodegeneration. Endocytosis is specifically needed for the degradation of membrane proteins whereas autophagy is responsible for the. The transcription factor eb tfeb, a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Tfeb coordinates the expression of proteins participating in the autophagy. Organelle biogenesis and autophagy molecular biology of. Tfeb regulates lysosomal proteostasis human molecular. After activation, tfeb and tfe3 translocate into the nucleus and transcriptionally induce the expression of multiple genes responsible for autophagy and lysosomal functions,,,46. The role of tfeb has been intensively studied in numerous neurodegenerative diseases, such as huntington disease, ad and pd. 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. Polyamines control eif5a hypusination, tfeb translation. Pdf autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Initially, we aimed to investigate the links between the p38 map kinase and tfeb and tfe3 by using p38 small molecule inhibitors. Enhancing lysosomal biogenesis and autophagic flux by activating.
Current understanding in regulation of lysosomal biogenesis and lysosomal function is still limited. Request pdf tfeb links autophagy to lysosomal biogenesis autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Lysosomes are the major catabolic compartment within eukaryotic cells, and their biogenesis requires the integration of the biosynthetic and endosomal pathways. Zkscan3 znf306 is a master transcriptional repressor of. Mammalian target of rapamycin mtor complex 1 mtorc1 is an important, highly conserved, regulator of cell growth. Cathepsin b can also mediate trypsinogen activation to promote the development of acute pancreatitis van acker et al. On the other hand, lysosomal biogenesis also requires the integration of. This file is now available in the html version of the article. Acetyl coenzyme a acetylcoa generated from glucose and acetate uptake is.
Alzheimers disease ad is one of the most common neurodegenerative diseases, and. The degradative pathway of macroautophagy has a critical role in many cellular processes. Tfeb an essential regulator of lysosome biogenesis. However, only several smallmolecule tfeb activators have been discovered and their neuroprotective effects in pd are unclear. Endocytosis and autophagy are the primary inputs of the lysosomal degradation pathway. Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. Cathepsin b modulates lysosomal biogenesis and host.
A number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes. Thus, increased lysosomal biogenesis accompanies the expanded autophagosome compartment in pda and may facilitate high levels of. The transcription factor eb tfeb is known to regulate expression of many genes involved in autophagy and lysosome biogenesis. They find that autophagy is maintained by spermidine via promoting eif5a function and tfeb translation. Temozolomideperillyl alcohol conjugate neo212, a novel temozolomide tmz analog, was previously reported to exert its anticancer effect in nonsmall cell lung cancer nsclc, and human nasopharyngeal carcinoma npc, etc in the current study, we intend to illuminate the potential anticancer property and the underly mechanisms of neo212 in ovarian cancer cells.
Tfeb direct targets have been identified by a combination of genomic and transcriptomic approaches and include lysosomal hydrolases, lysosomal membrane proteins and proteins associated with lysosomal biogenesis and autophagy. Tfeb links autophagy to lysosomal biogenesis request pdf. The transcription factors tfe3 and tfeb amplify p53. The transcription factor eb tfeb, a main regulating factor of autophagy and lysosome biosynthesis, is involved in the pathogenesis of ad by regulating autophagylysosomal pathways. However, the interplay between endosomes and mtorc1 is poorly. Transcriptional control of the autophagylysosome system in pancreatic cancer. P2x7 induces lysosomal biogenesis via ampk pathway. Altered tfebmediated lysosomal biogenesis in gaucher. Tfeb links autophagy to lysosomal biogenesis science. Induction of autophagy and lysosomal biogenesis by transcription factor eb tfeb nuclear translocation can rescue fibrotic diseases. A curcumin derivative activates tfeb and protects against. 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. Exploiting macrophage autophagylysosomal biogenesis as a.