A Gene Network Regulating Lysosomal Biogenesis and Function
Abstract
Master Controller: Cellular organelles allow the localized regulation of specialized processes. Under certain conditions, such as increased growth, organelles may be required to alter their function. Coordinated regulation of the gene networks required for mitochondrial and endoplasmic reticulum function has been observed. Now, Sardiello et al. (p. 473 ; published online 25 June) have discovered a gene network regulating the lysosome, the major organelle involved in the degradation of internalized macromolecules. Many lysosomal genes were regulated by a single transcription factor, TFEB. TFEB itself can be activated when the lysosome malfunctions and can regulate both the abundance of lysosomes found in the cell, as well as the ability to degrade complex molecules, including a mutant protein that accumulates in patients with Huntington's disease. These results may have implications for the treatment of human lysosomal storage disorders, which are characterized by the aberrant accumulation of macromolecules causing cellular dysfunction.
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TFE3 and TFEB are two major members of the MiT/TFE subfamily and are well characterized as master regulators of lysosome biogenesis and autophagy.
“Transcription factor E3 (TFE3) and transcription factor EB (TFEB) are two major members of the microphthalmia-transcription factor E (MiT/TFE) subfamily and well characterized as master regulators of lysosome biogenesis and autophagy1–4.”
From PDCD4 triggers α-synuclein accumulation and motor deficits via co-suppressing TFE3 and TFEB translation in a model of Parkinson’s disease (2024) · cites this paper as [2]
A gene regulatory network named CLEAR (coordinated lysosomal enhancement and regulation) that controls both lysosome and autophagosome biogenesis was identified using a systems-biology approach.
“A gene regulatory network, named CLEAR (coordinated lysosomal enhancement and regulation) that controls both lysosome and autophagosome biogenesis was identified using a systemsbiology approach.[463][464][465]”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [464]
Overexpression or post-translational activation of the gene encoding TFEB induces autophagy; TFEB is a transcriptional regulator of the biogenesis of both lysosomes and autophagosomes.
“For example, this can be achieved either through overexpression or post-translational activation of the gene encoding TFEB (see Transcriptional and translational regulation), a transcriptional regulator of the biogenesis of both lysosomes and autophagosomes.463,464”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [464]
These included lysosomal enzymes ASAH1, LIPA, CTSA, CTSG, CTSZ, PLA2G15 and PPT1, part of the CLEAR network, as well as PLA2G7.
“Notably, these included the lysosomal enzymes ASAH1, LIPA, CTSA, CTSG, CTSZ, PLA2G15 and PPT1, enzymes part of the Coordinated Lysosomal Expression and Regulation network60, as well as PLA2G7, previously associated with atherosclerotic plaques61 and with the LAM48 and MIMS-foamy microglial states11.”
From Foamy microglia link oxylipins to disease progression in multiple sclerosis (2026) · cites this paper as [60]
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 [28]
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 [28]
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 [28]
TFEB directs expression of autophagy and lysosomal genes comprising the CLEAR network by binding to a conserved promoter motif.
“Global regulation of the myriad effectors and phases of autophagy is overseen by TFEB (transcription factor EB), a basic helix-loop-helix leucine zipper that directs expression of autophagy and lysosomal genes comprising the coordinated lysosomal expression and regulation (CLEAR) network by binding to a conserved promoter motif [47,48].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [47]
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- Authors
- Sardiello, M., Palmieri, M., di Ronza, A., Medina, D. L., Valenza, M., Gennarino, V. A., Di Malta, C., Donaudy, F., Embrione, V., Polishchuk, R. S., Banfi, S., Parenti, G., Cattaneo, E., & Ballabio, A.
- Affiliations
- Telethon Institute Of Genetics And Medicine (IT)
- Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Naples, Italy.
- University of Milan (IT)
- Telethon Electron Microscopy Core Facility, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, I-66030 Santa Maria Imbaro, Chieti, Italy.
- Federico II University Hospital (IT)
- Corresponding author
- Ballabio, Andrea
- ORCID
- Venue
- Science
- Published
- 2009-07-24
- Volume
- 325
- Issue
- 5939
- Pages
- 473-477
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2077499130
- Cited by
- 2,543
- References
- 26
- Citations by year
- 2026: 180 · 2025: 173 · 2024: 214 · 2023: 196 · 2022: 218 · 2021: 224 · 2020: 241 · 2019: 179 · 2018: 191 · 2017: 147 · 2016: 152 · 2015: 121 · 2014: 88 · 2013: 73 · 2012: 66
- FWCI
- 31.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- lysosomal biogenesis, TFEB, transcription factors, gene regulatory networks, lysosomes, autophagy, lysosomal storage disease, Huntington's disease, protein degradation, lysosomal dysfunction
- MeSH terms
- Animals, Cells, Cultured, HeLa Cells, Humans, Lysosomes, Promoter Regions, Genetic, Sucrose, Transcription Factors, Consensus Sequence, Chromatin Immunoprecipitation, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Gene Regulatory Networks, Inverted Repeat Sequences
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