TFEB regulates lysosomal proteostasis
Abstract
Loss-of-function diseases are often caused by destabilizing mutations that lead to protein misfolding and degradation. Modulating the innate protein homeostasis (proteostasis) capacity may lead to rescue of native folding of the mutated variants, thereby ameliorating the disease phenotype. In lysosomal storage disorders (LSDs), a number of highly prevalent alleles have missense mutations that do not impair the enzyme's catalytic activity but destabilize its native structure, resulting in the degradation of the misfolded protein. Enhancing the cellular folding capacity enables rescuing the native, biologically functional structure of these unstable mutated enzymes. However, proteostasis modulators specific for the lysosomal system are currently unknown. Here, we investigate the role of the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and function, in modulating lysosomal proteostasis in LSDs. We show that TFEB activation results in enhanced folding, trafficking and lysosomal activity of a severely destabilized glucocerebrosidase (GC) variant associated with the development of Gaucher disease (GD), the most common LSD. TFEB specifically induces the expression of GC and of key genes involved in folding and lysosomal trafficking, thereby enhancing both the pool of mutated enzyme and its processing through the secretory pathway. TFEB activation also rescues the activity of a β-hexosaminidase mutant associated with the development of another LSD, Tay-S…
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The lysosomal biogenesis list resulted from an extensive literature analysis combining data that underwent previous experimental validation.
“The “lysosomal biogenesis list” resulted instead from an extensive literature analysis, obtained by combining data that underwent previous experimental validation [15, 18, 19, 28–30].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [30]
The authors identified 26 targets to assess the state of lysosomal biogenesis.
“Hence, for the second sub-lists, we identified 26 targets to assess the state of lysosomal biogenesis (Fig. 2) at variance with the autophagy activation list, this sub-list has been realized by only comparing data from recent work, in which mRNA levels of lysosomal genes in response to autophagy enhancement were accurately and experimentally examined [15, 18, 19, 28–30].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [30]
The list for the evaluation of "lysosomal biogenesis" was created from literature by combining data that underwent preceding experimental validation.
“Similarly, the list for the evaluation of “lysosomal biogenesis” was created from literature by combining data that underwent preceding experimental validation [15, 18, 19, 28–30].”
From A gene toolbox for monitoring autophagy transcription (2021) · cites this paper as [30]
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
TFEB Links Autophagy to Lysosomal Biogenesis
Settembre, C., Di Malta, C., Polito, V. A., Arencibia, M. G., Vetrini, F., Erdin, S., Erdin, S. U., Huynh, T., Medina, D., Colella, P., et al. (2011) · Science · doi:10.1126/science.1204592 · Cited by 3,365 · see citing works
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The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective
Martini-Stoica, H., Xu, Y., Ballabio, A., & Zheng, H. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.02.002 · Cited by 436 · see citing works
Lysosomal storage diseases: from pathophysiology to therapy
Parenti, G., Andria, G., & Ballabio, A. (2015) · Annual Review of Medicine · doi:10.1146/annurev-med-122313-085916 · Cited by 404 · see citing works
TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading
Martini-Stoica, H., Cole, A. L., Swartzlander, D. B., Chen, F., Wan, Y.-W., Bajaj, L., Bader, D. A., Lee, V. M. Y., Trojanowski, J. Q., Liu, Z., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20172158 · Cited by 253 · see citing works
Self-citationLysosome biogenesis in health and disease
Bajaj, L., Lotfi, P., Pal, R., Ronza, A. D., Sharma, J., & Sardiello, M. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14564 · Cited by 153 · see citing works
Self-citationChandra, S., Jana, M., & Pahan, K. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.0054-18.2018 · Cited by 134 · see citing works
A gene toolbox for monitoring autophagy transcription
Bordi, M., De Cegli, R., Testa, B., Nixon, R. A., Ballabio, A., & Cecconi, F. (2021) · Cell Death & Disease · doi:10.1038/s41419-021-04121-9 · Cited by 131 · see citing works
Lotfi, P., Tse, D. Y., Di Ronza, A., Seymour, M. L., Martano, G., Cooper, J. D., Pereira, F. A., Passafaro, M., Wu, S. M., & Sardiello, M. (2018) · Autophagy · doi:10.1080/15548627.2018.1474313 · Cited by 106 · see citing works
Self-citationPoly (ADP-ribose) polymerase 1 and neurodegenerative diseases: past, present, and future
Hu, M.-L., Pan, Y.-R., Yong, Y.-Y., Liu, Y., Yu, L., Qin, D.-L., Qiao, G., Law, B. Y.-K., Wu, J.-M., Zhou, X.-G., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102078 · Cited by 44 · see citing works
USP7 protects TFEB from proteasome-mediated degradation
Keshri, S., Vicinanza, M., Takla, M., & Rubinsztein, D. C. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114872 · Cited by 8 · see citing works
- Authors
- Song, W., Wang, F., Savini, M., Ake, A., di Ronza, A., Sardiello, M., & Segatori, L.
- Affiliations
- Rice University (US)
- Baylor College of Medicine (US)
- Corresponding author
- Segatori, Laura
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-02-07
- Volume
- 22
- Issue
- 10
- Pages
- 1994-2009
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2118611462
- Cited by
- 143
- References
- 2
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 10 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 10 · 2019: 16 · 2018: 14 · 2017: 12 · 2016: 13 · 2015: 7 · 2014: 14 · 2013: 3
- FWCI
- 8.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Rice Research Repository (Rice University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- TFEB, lysosomal storage disease, Gaucher disease, Tay-Sachs disease, glucocerebrosidase, beta-hexosaminidase, protein misfolding, protein destabilization, missense mutations, protein folding, lysosomal trafficking, secretory pathway, transcriptional regulation, therapeutic target
- MeSH terms
- Cells, Cultured, Fibroblasts, Gaucher Disease, Gene Expression Regulation, Glucosylceramidase, Homeostasis, Humans, Lysosomes, Mutation, Tay-Sachs Disease, Protein Folding, Protein Transport, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Proteolysis
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