scholarly journals Genistein Activates Transcription Factor EB and Corrects Niemann–Pick C Phenotype

2021 ◽  
Vol 22 (8) ◽  
pp. 4220
Author(s):  
Graciela Argüello ◽  
Elisa Balboa ◽  
Pablo J. Tapia ◽  
Juan Castro ◽  
María José Yañez ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Culture Media ◽  
Autophagic Flux ◽  
Lysosomal Storage ◽  
Cholesterol Accumulation ◽  
Activation Of Transcription ◽  
Genistein Treatment ◽  
Transcription Factor Eb ◽  
Function Regulator ◽  
Niemann Pick

Niemann–Pick type C disease (NPCD) is a lysosomal storage disease (LSD) characterized by abnormal cholesterol accumulation in lysosomes, impaired autophagy flux, and lysosomal dysfunction. The activation of transcription factor EB (TFEB), a master lysosomal function regulator, reduces the accumulation of lysosomal substrates in LSDs where the degradative capacity of the cells is compromised. Genistein can pass the blood–brain barrier and activate TFEB. Hence, we investigated the effect of TFEB activation by genistein toward correcting the NPC phenotype. We show that genistein promotes TFEB translocation to the nucleus in HeLa TFEB-GFP, Huh7, and SHSY-5Y cells treated with U18666A and NPC1 patient fibroblasts. Genistein treatment improved lysosomal protein expression and autophagic flux, decreasing p62 levels and increasing those of the LC3-II in NPC1 patient fibroblasts. Genistein induced an increase in β-hexosaminidase activity in the culture media of NPC1 patient fibroblasts, suggesting an increase in lysosomal exocytosis, which correlated with a decrease in cholesterol accumulation after filipin staining, including cells treated with U18666A and NPC1 patient fibroblasts. These results support that genistein-mediated TFEB activation corrects pathological phenotypes in NPC models and substantiates the need for further studies on this isoflavonoid as a potential therapeutic agent to treat NPCD and other LSDs with neurological compromise.

scholarly journals Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation

2015 ◽  
Vol 112 (11) ◽  
pp. E1373-E1381 ◽  
Author(s):  
Wuyang Wang ◽  
Qiong Gao ◽  
Meimei Yang ◽  
Xiaoli Zhang ◽  
Lu Yu ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Control Process ◽  
Nutrient Starvation ◽  
Lysosomal Storage ◽  
Activation Of Transcription ◽  
Quality Control Process ◽  
Transcription Factor Eb ◽  
Niemann Pick ◽  
Starvation Effect ◽  
Cellular Components

Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca2+ channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca2+ imaging and whole-lysosome patch clamping, lysosomal Ca2+ release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na+-selective currents were not up-regulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann–Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca2+ signaling.

scholarly journals Optical induction of autophagy viaTranscription factor EB(TFEB) reduces pathological tau in neurons

2019 ◽  
Author(s):  
JL Binder ◽  
V Deretic ◽  
JP Weick ◽  
K Bhaskar
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Expression System ◽  
Autophagic Flux ◽  
Over Expression ◽  
Bacterial Transcription ◽  
Transcription Factor Eb ◽  
Cellular Bioenergetics ◽  
Human Ipsc ◽  
First Time

AbstractAggregation and accumulation of microtubule associated protein tau in neurons is major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Attempts have been made to promote clearance of pathological tau (p-Tau) from neurons via autophagy. Over expression of transcription factor EB (TFEB), has shown to clear pTau from neurons via autophagy. However, sustained TFEB activation and/or autophagy can create burden on cellular bioenergetics and can be deleterious. Thus, we engineered a minimally invasive optical system that could transiently alter autophagic flux. We optimized and tested an optogenetic gene expression system derived from a previously engineered bacterial transcription factor, EL222. For the first time, our group utilized this system not only to spatial-temporally control nuclear TFEB expression, we also show light-induced TFEB has the capacity to reduce p-Tau burden in AD patient-derived human iPSC-neurons. Together, these results suggest that optically-regulatable gene expression of TFEB unlocks opto-therapeutics to treat AD and other dementias.

scholarly journals Targeting defective sphingosine kinase 1 in Niemann–Pick type C disease with an activator mitigates cholesterol accumulation

2020 ◽  
Vol 295 (27) ◽  
pp. 9121-9133 ◽  
Author(s):  
Jason Newton ◽  
Elisa N. D. Palladino ◽  
Cynthia Weigel ◽  
Michael Maceyka ◽  
Markus H. Gräler ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Sphingosine Kinase ◽  
Autophagic Flux ◽  
Sphingosine Kinase 1 ◽  
Cholesterol Trafficking ◽  
Cholesterol Accumulation ◽  
Cellular Models ◽  
Ester Formation ◽  
Type C ◽  
Niemann Pick

Niemann–Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

scholarly journals Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy-lysosome pathway

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jie Xu ◽  
Xiao-Qi Zhang ◽  
Zaijun Zhang
Keyword(s):  
Transcription Factor ◽  
Natural Products ◽  
Chinese Medicine ◽  
Degradation Process ◽  
Human Diseases ◽  
Lysosomal Storage ◽  
Toxic Protein ◽  
Intracellular Proteins ◽  
Transcription Factor Eb ◽  
Storage Disorders

AbstractAutophagy is a highly conserved degradation process for long-lived intracellular proteins and organelles mediated by lysosomes. Deficits in the autophagy-lysosome pathway (ALP) have been linked to a variety of human diseases, including neurodegenerative diseases, lysosomal storage disorders, and cancers. Transcription factor EB (TFEB) has been identified as a major regulator of autophagy and lysosomal biogenesis. Increasing evidence has demonstrated that TFEB activation can promote the clearance of toxic protein aggregates and regulate cellular metabolism. Traditional Chinese medicine (TCM)-derived natural products as important sources for drug discovery have been widely used for the treatment of various diseases associated with ALP dysfunction. Herein, we review (1) the regulation of TFEB and ALP; (2) TFEB and ALP dysregulation in human diseases; (3) TFEB activators from natural products and their potential uses.

scholarly journals Rag GTPases mediate amino acid–dependent recruitment of TFEB and MITF to lysosomes

2013 ◽  
Vol 200 (4) ◽  
pp. 475-491 ◽  
Author(s):  
Jose A. Martina ◽  
Rosa Puertollano
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Energy Levels ◽  
Control Of Gene Expression ◽  
Rag Gtpases ◽  
Activation Of Transcription ◽  
Switch Regions ◽  
Transcription Factor Eb ◽  
Cell Growth And Proliferation

The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.

Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy

2016 ◽  
Vol 473 (21) ◽  
pp. 3769-3789 ◽  
Author(s):  
Jordan J. Bartlett ◽  
Purvi C. Trivedi ◽  
Pollen Yeung ◽  
Petra C. Kienesberger ◽  
Thomas Pulinilkunnil
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Cathepsin B ◽  
Ex Vivo ◽  
Calcium Flux ◽  
Autophagic Flux ◽  
Mitochondrial Energy Metabolism ◽  
Transcription Factor Eb

Doxorubicin (DOX) is an effective anti-cancer agent. However, DOX treatment increases patient susceptibility to dilated cardiomyopathy. DOX predisposes cardiomyocytes to insult by suppressing mitochondrial energy metabolism, altering calcium flux, and disrupting proteolysis and proteostasis. Prior studies have assessed the role of macroautophagy in DOX cardiotoxicity; however, limited studies have examined whether DOX mediates cardiac injury through dysfunctions in inter- and/or intra-lysosomal signaling events. Lysosomal signaling and function is governed by transcription factor EB (TFEB). In the present study, we hypothesized that DOX caused myocyte injury by impairing lysosomal function and signaling through negative regulation of TFEB. Indeed, we found that DOX repressed cellular TFEB expression, which was associated with impaired cathepsin proteolytic activity across in vivo, ex vivo, and in vitro models of DOX cardiotoxicity. Furthermore, we observed that loss of TFEB was associated with reduction in macroautophagy protein expression, inhibition of autophagic flux, impairments in lysosomal cathepsin B activity, and activation of cell death. Restoration and/or activation of TFEB in DOX-treated cardiomyocytes prevented DOX-induced suppression of cathepsin B activity, reduced DOX-mediated reactive oxygen species (ROS) overproduction, attenuated activation of caspase-3, and improved cellular viability. Collectively, loss of TFEB inhibits lysosomal autophagy, rendering cardiomyocytes susceptible to DOX-induced proteotoxicity and injury. Our data reveal a novel mechanism wherein DOX primes cardiomyocytes for cell death by depleting cellular TFEB.

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