Journal ArticleDOI
Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response.
Se Jin Jeong,Jeremiah Stitham,Trent D. Evans,Xiangyu Zhang,Astrid Rodriguez-Velez,Yu Sheng Yeh,Joan Tao,Koki Takabatake,Slava Epelman,Irfan J. Lodhi,Joel D. Schilling,Brian J. DeBosch,Abhinav Diwan,Abhinav Diwan,Babak Razani,Babak Razani +15 more
TLDR
In this article, Trehalose is shown to act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation and nuclear translocation.Abstract:
The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system.Abbreviations: ASO: antisense oligonucleotide; AU: arbitrary units; BMDM: bone marrow-derived macrophages; CLFs: crude lysosomal fractions; CTSD: cathepsin D; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; MAP1LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTORC1: mechanistic target of rapamycin kinase complex 1; pMAC: peritoneal macrophages; SLC2A8/GLUT8: solute carrier family 2, (facilitated glucose transporter), member 8; TFEB: transcription factor EB; TMR: tetramethylrhodamine; TREH: trehalase.read more
Citations
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Research Hotspots and Trends Analysis of TFEB: A Bibliometric and Scientometric Analysis
TL;DR: In this paper , the authors explore the development context, research hotspots and frontiers of Transcription Factor EB (TFEB) from 1991 to 2021 by bibliometric analysis.
Journal ArticleDOI
TFEB coordinates autophagy and pyroptosis as hepatotoxicity responses to ZnO nanoparticles.
Xingyao Pei,Ding Xuefen Liu,Jian Li,Liuan Li,Xiangbin Ding,Wenjuan Zhang,Zibin Li,Gang Xu,Cun Li,Daowen Li +9 more
TL;DR: Zhang et al. as mentioned in this paper clarified hepatotoxic mechanism of ZnO NPs through investigating the crosstalk between autophagy and pyroptosis in hepatocyte.
Journal ArticleDOI
Current Status of Autophagy Enhancers in Metabolic Disorders and Other Diseases
Kihyoun Park,Myung-Shik Lee +1 more
TL;DR: The role of autophagy in the homeostasis and physiology of the individual tissues and whole organism in vivo has been incriminated in the pathogenesis of a variety of diseases including metabolic diseases, neurodegenerative diseases, cardiovascular diseases, inflammatory or immunological disorders, cancer and aging as discussed by the authors .
Journal ArticleDOI
The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases
TL;DR: The regulation of TFEB expression and its functions in ALP are delineated and the protective effects and molecular mechanisms of some TFEBs-targeted agonists in neurodegenerative diseases are summarized.
Journal ArticleDOI
Potential Diets to Improve Mitochondrial Activity in Amyotrophic Lateral Sclerosis
TL;DR: A growing body of evidence shows that more efficient mitophagy could prevent and/or treat this disorder by suppressing mitochondrial dysfunction-induced oxidative stress and inflammation, which could translate into a treatment for neurodegenerative diseases, including ALS as discussed by the authors .
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