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Updated: Feb 10, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
The complex relationship between TFEB transcription factor phosphorylation and subcellular localization
Rosa Puertollano1, Shawn M Ferguson2,3, James Brugarolas4,5
1Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA puertolr@nhlbi.nih.gov shawn.ferguson@yale.edu James.Brugarolas@utsouthwestern.edu ballabio@tigem.it.
Abstract:
The MiT-TFE family of basic helix-loop-helix leucine-zipper transcription factors includes four members: TFEB, TFE3, TFEC, and MITF Originally described as oncogenes, these factors play a major role as regulators of lysosome biogenesis, cellular energy homeostasis, and autophagy. An important mechanism by which these transcription factors are regulated involves their shuttling between the surface of lysosomes, the cytoplasm, and the nucleus. Such dynamic changes in subcellular localization occur in response to nutrient fluctuations and various forms of cell stress and are mediated by changes in the phosphorylation of multiple conserved amino acids. Major kinases responsible for MiT-TFE protein phosphorylation include mTOR, ERK, GSK3, and AKT In addition, calcineurin de-phosphorylates MiT-TFE proteins in response to lysosomal calcium release. Thus, through changes in the phosphorylation state of MiT-TFE proteins, lysosome function is coordinated with the cellular metabolic state and cellular demands. This review summarizes the evidence supporting MiT-TFE regulation by phosphorylation at multiple key sites. Elucidation of such regulatory mechanisms is of fundamental importance to understand how these transcription factors contribute to both health and disease.
Insights
The MiT-TFE family of transcription factors regulates cell functions like autophagy. Their activity is controlled by phosphorylation, linking cell stress and metabolism to lysosome function.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The Mi-TFE transcription factor family (TFEB, TFE3, TFEC, MITF) are key regulators of cellular processes.
- Initially identified as oncogenes, they are now recognized for their roles in lysosome biogenesis, energy balance, and autophagy.
- Their function is tightly controlled by dynamic changes in subcellular localization.
Purpose of the Study:
- To review the regulatory mechanisms of Mi-TFE transcription factors, focusing on phosphorylation.
- To elucidate how phosphorylation controls Mi-TFE localization and function in response to cellular signals.
- To highlight the importance of these regulatory mechanisms in cellular homeostasis and disease.
Main Methods:
- This review synthesizes existing research on Mi-TFE transcription factors.
- It examines the role of kinases (mTOR, ERK, GSK3, AKT) and phosphatases (calcineurin) in regulating Mi-TFE phosphorylation.
- Evidence for phosphorylation at multiple key sites influencing subcellular localization is summarized.
Main Results:
- Mi-TFE proteins shuttle between lysosomes, cytoplasm, and nucleus in response to nutrient availability and cell stress.
- Phosphorylation by specific kinases and dephosphorylation by calcineurin mediate these localization changes.
- These post-translational modifications link lysosome function to the cell's metabolic state and demands.
Conclusions:
- Mi-TFE regulation by phosphorylation is a critical mechanism coordinating cellular metabolism, lysosome function, and stress responses.
- Understanding these phosphorylation-dependent regulatory networks is crucial for comprehending Mi-TFE roles in health and disease.
- Further research into these pathways may reveal therapeutic targets for diseases involving lysosomal dysfunction or altered cellular metabolism.
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