scholarly journals Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Huifeng Pi ◽  
Min Li ◽  
Li Tian ◽  
Zhiqi Yang ◽  
Zhengping Yu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Autophagic Flux ◽  
Transcription Factor Eb

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.

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.

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 Blockage of Extracellular Signal-Regulated Kinase Exerts an Antitumor Effect via Regulating Energy Metabolism and Enhances the Efficacy of Autophagy Inhibitors by Regulating Transcription Factor EB Nuclear Translocation in Osteosarcoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Man Zhang ◽  
Yang Bai ◽  
Chang Xu ◽  
Yiying Qi ◽  
Jiahong Meng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nuclear Translocation ◽  
Aerobic Glycolysis ◽  
Autophagic Flux ◽  
Antitumor Activities ◽  
Extracellular Signal Regulated Kinase ◽  
Clinical Phase ◽  
Extracellular Signal ◽  
Transcription Factor Eb ◽  
Mitochondria Pathway

Accumulating evidence suggests that extracellular signal-regulated kinase (ERK) is a valuable target molecule for cancer. However, antitumor drugs targeting ERK are still in their clinical phase and no FDA-approved medications exist. In this study, we identified an ERK inhibitor (ERKi; Vx-11e) with potential antitumor activities, which was reflected by the inhibition in the survival and proliferation of Osteosarcoma (OS) cells. Mechanistically, the ERKi regulated autophagic flux by promoting the translocation of transcription factor EB (TFEB) in OS cells, thereby increasing the dependence of OS cells on autophagy and sensitivity to treatment with autophagy inhibitors in OS. Besides, we also found that the ERKi could regulate mitochondrial apoptosis through the ROS/mitochondria pathway and aerobic glycolysis in OS, which also increases the dependence of OS cells on autophagy to clear metabolites to a certain extent. These results may provide a reference for the clinically improved efficacy of ERKis in combination with autophagy inhibitors in the treatment of OS and indicate its potential as a therapeutic agent.

scholarly journals Apolipoprotein M attenuates doxorubicin cardiotoxicity by regulating transcription factor EB

2021 ◽  
Author(s):  
Zhen Guo ◽  
Antonino Picataggi ◽  
Carla Valenzuela Ripoll ◽  
Ezhilarasi Chendamarai ◽  
Amanda Girardi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Plasma Protein ◽  
Nuclear Translocation ◽  
Density Lipoprotein ◽  
Autophagic Flux ◽  
Human Heart Failure ◽  
Apolipoprotein M ◽  
Protein Levels ◽  
Doxorubicin Cardiotoxicity ◽  
Transcription Factor Eb

AbstractApolipoprotein M (ApoM) is an apolipoprotein that binds sphingosine-1-phosphate (S1P) and high-density lipoprotein. ApoM, via S1P signaling, is thought to protect cardiomyocytes from apoptosis, and ApoM plasma protein levels are inversely associated with increased mortality risk in human heart failure. Here, using a doxorubicin cardiotoxicity model, we identify ApoM as a novel regulator of myocardial autophagy. Doxorubicin treatment reduces ApoM plasma protein levels in wild-type mice and humans. Hepatic ApoM transgenic overexpression (ApomTG) protects mice from reductions in cardiac function observed in littermate controls. Though ApoM did not alter markers of DNA damage, apoptosis, Akt signaling, or fibrosis, ApoM prevented doxorubicin-induced reductions in autophagic flux. In the murine myocardium, doxorubicin reduced the nuclear protein content of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, in control mice but not ApomTG mice. Furthermore, adeno-associated virus 9 mediated knockdown of TFEB reversed the beneficial effects of ApoM on the myocardium, leading to cardiomyopathy and mortality in ApomTG mice. Our studies provide a mechanistic link between ApoM and the autophagy-lysosome pathway in the murine heart. Our clinical observations that reduced ApoM is associated with mortality may be explained by its role in sustaining autophagy.One sentence summaryApolipoprotein M attenuates doxorubicin cardiotoxicity by preserving nuclear translocation of TFEB and autophagic flux.

scholarly journals Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Inflammatory Responses ◽  
Tissue Samples ◽  
Protein Levels ◽  
Virus Serotype ◽  
Transcription Factor Eb ◽  
The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

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