TFEB

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Protein-coding gene in the species Homo sapiens

title: "TFEB" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Protein-coding gene in the species Homo sapiens" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/TFEB" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Protein-coding gene in the species Homo sapiens ::

Transcription factor EB is a protein that in humans is encoded by the TFEB gene.

Function

TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. Upon nutrient depletion and under aberrant lysosomal storage conditions such as in lysosomal storage diseases, TFEB translocates from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy.

In bacterial infection nicotinic acid adenine dinucleotide phosphate (NAADP) induction of lysosomal Ca2+ efflux and TFEB activation leads to enhanced expression of inflammatory cytokines. Viral-mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as Huntington, Parkinson and Alzheimer diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes. TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease.

TFEB overexpression has been found in patients with renal cell carcinoma and pancreatic cancer and was shown to promote tumorogenesis via induction of various oncogenic signals.

TFEB constitutive activation, due to FLCN mutations, drives renal cystogenesis and tumorigenesis in Birt–Hogg–Dubé syndrome.

Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2).

mTORC1 phosphorylation of TFEB occurs at the lysosomal surface, both of which are localized there by interaction with the Rag GTPases. Phosphorylated TFEB is then retained in the cytosol by interaction with 14-3-3 proteins. These kinases are tuned to the levels of extracellular nutrients suggesting a coordination in regulation of autophagy and lysosomal biogenesis and partnership of two distinct cellular organelles. Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin.

TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation.

TFEB is also a target of the protein kinase AKT/PKB. AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation. Pharmacological inhibition of AKT/PKB activates TFEB, promotes lysosome biogenesis and autophagy, and ameliorates neuropathology in mouse models of Juvenile Batten disease and Sanfilippo syndrome type B.

TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.

References

References

  1. (Aug 1990). "A helix-loop-helix protein related to the immunoglobulin E box-binding proteins". Molecular and Cellular Biology.
  2. "Entrez Gene: TFEB transcription factor EB".
  3. (Jul 2009). "A gene network regulating lysosomal biogenesis and function". Science.
  4. (Jun 2011). "TFEB links autophagy to lysosomal biogenesis". Science.
  5. (Sep 2011). "Transcriptional activation of lysosomal exocytosis promotes cellular clearance". Developmental Cell.
  6. (2020). "NAD + metabolism: pathophysiologic mechanisms and therapeutic potential". [[Signal Transduction and Targeted Therapy]].
  7. (Jun 2013). "TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop". Nature Cell Biology.
  8. (Sep 2014). "Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB". EMBO Molecular Medicine.
  9. (May 2013). "TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity". Proc Natl Acad Sci USA.
  10. (Jul 2012). "PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function". Science Translational Medicine.
  11. (Jun 2017). "Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth". Science.
  12. (Sep 2016). "Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling". eLife.
  13. (Aug 2015). "Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism". Nature.
  14. (Sep 2020). "A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome". Nature.
  15. (Mar 2012). "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB". EMBO Journal.
  16. (Jun 2012). "MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB". Autophagy.
  17. (Jun 2012). "The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis". Science Signaling.
  18. (Jun 2013). "RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis". Autophagy.
  19. (Mar 2015). "Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB". Nature Cell Biology.
  20. (Aug 2018). "mTOR-dependent phosphorylation controls TFEB nuclear export". Nature Communications.
  21. "A TFEB nuclear export signal integrates amino acid supply and glucose availability". Nature Communications.
  22. (Feb 2017). "mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases". Nature Communications.
  23. (Jul 2018). "Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency". Autophagy.
  24. (Jan 2013). "Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes". Nature Immunology.

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