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Jeong SJ, Stitham J, Evans TD, et al. Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response. Autophagy. 2021;17(11):3740-3752doi: 10.1080/15548627.2021.1896906.
Jeong, S. J., Stitham, J., Evans, T. D., Zhang, X., Rodriguez-Velez, A., Yeh, Y. S., Tao, J., Takabatake, K., Epelman, S., Lodhi, I. J., Schilling, J. D., DeBosch, B. J., Diwan, A., & Razani, B. (2021). Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response. Autophagy, 17(11), 3740-3752. https://doi.org/10.1080/15548627.2021.1896906
Jeong, Se-Jin, et al. "Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response." Autophagy vol. 17,11 (2021): 3740-3752. doi: https://doi.org/10.1080/15548627.2021.1896906
Jeong SJ, Stitham J, Evans TD, Zhang X, Rodriguez-Velez A, Yeh YS, Tao J, Takabatake K, Epelman S, Lodhi IJ, Schilling JD, DeBosch BJ, Diwan A, Razani B. Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response. Autophagy. 2021 Nov;17(11):3740-3752. doi: 10.1080/15548627.2021.1896906. Epub 2021 Mar 11. PMID: 33706671; PMCID: PMC8632292.
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Autophagy. 2021 Nov;17(11):3740-3752. doi: 10.1080/15548627.2021.1896906. Epub 2021 Mar 11.

Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response.

Autophagy

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, Babak Razani

Affiliations

  1. Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA.
  2. Department of Medicine, Division of Endocrinology, Metabolism, Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.
  3. Peter Munk Cardiac Center, Ted Rogers Centre for Heart Failure Research and the Toronto General Hospital Research Institute, University of Toronto, Toronto, ON, Canada.
  4. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  5. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
  6. John Cochran VA Medical Center, St. Louis, MO, USA.

PMID: 33706671 PMCID: PMC8632292 DOI: 10.1080/15548627.2021.1896906

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.

Keywords: Endocytosis; MTORC1; TFEB; lysosome; trehalose

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