Biology:TFEB

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Generic protein structure example

Transcription factor EB is a protein that in humans is encoded by the TFEB gene.[1][2]

Function

TFEB is a master gene for lysosomal biogenesis.[3] It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy.[3][4] 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.[3][4] TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy. [3][4][5] 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.[3][5][6][7][8] TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease.[9] TFEB overexpression has been found in patients with renal cell carcinoma and pancreatic cancer and was shown to promote tumorogenesis via induction of varius oncogenic signals.[10][11][12]

Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2). [4][13][14][15] 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.[14][16][15] 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.[4] Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin. [17] TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation.[18][19] TFEB is also a target of the protein kinase AKT/PKB.[20] AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation.[20] 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.[20][21] TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.[22]

References

  1. ↑ "A helix-loop-helix protein related to the immunoglobulin E box-binding proteins". Molecular and Cellular Biology 10 (8): 4384–8. Aug 1990. doi:10.1128/mcb.10.8.4384. PMID 2115126. 
  2. ↑ "Entrez Gene: TFEB transcription factor EB". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7942. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "A gene network regulating lysosomal biogenesis and function". Science 325 (5939): 473–7. Jul 2009. doi:10.1126/science.1174447. PMID 19556463. Bibcode: 2009Sci...325..473S. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "TFEB links autophagy to lysosomal biogenesis". Science 332 (6036): 1429–33. Jun 2011. doi:10.1126/science.1204592. PMID 21617040. Bibcode: 2011Sci...332.1429S. 
  5. ↑ 5.0 5.1 "Transcriptional activation of lysosomal exocytosis promotes cellular clearance". Developmental Cell 21 (3): 421–30. Sep 2011. doi:10.1016/j.devcel.2011.07.016. PMID 21889421. 
  6. ↑ "TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop". Nature Cell Biology 15 (6): 647–58. Jun 2013. doi:10.1038/ncb2718. PMID 23604321. 
  7. ↑ "Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB". EMBO Molecular Medicine 6 (9): 1142–60. Sep 2014. doi:10.15252/emmm.201303671. PMID 25069841. 
  8. ↑ "TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity". Proc Natl Acad Sci USA 110 (19): 1817–26. May 2013. doi:10.1073/pnas.1305623110. PMID 23610405. Bibcode: 2013PNAS..110E1817D. 
  9. ↑ "PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function". Science Translational Medicine 4 (142): 142ra97. Jul 2012. doi:10.1126/scitranslmed.3003799. PMID 22786682. 
  10. ↑ "Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth". Science 356 (6343): 1188–1192. Jun 2017. doi:10.1126/science.aag2553. PMID 28619945. 
  11. ↑ "Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling". eLife 5. Sep 2016. doi:10.7554/eLife.17047. PMID 27668431. 
  12. ↑ "Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism". Nature 524 (7565): 361–5. Aug 2015. doi:10.1038/nature14587. PMID 26168401. Bibcode: 2015Natur.524..361P. 
  13. ↑ "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB". EMBO Journal 31 (5): 1095–108. Mar 2012. doi:10.1038/emboj.2012.32. PMID 22343943. 
  14. ↑ 14.0 14.1 "MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB". Autophagy 8 (6): 903–14. Jun 2012. doi:10.4161/auto.19653. PMID 22576015. 
  15. ↑ 15.0 15.1 "The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis". Science Signaling 5 (228): ra42. Jun 2012. doi:10.1126/scisignal.2002790. PMID 22692423. 
  16. ↑ "RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis". Autophagy 9 (6): 928–30. Jun 2013. doi:10.4161/auto.24371. PMID 23524842. 
  17. ↑ "Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB". Nature Cell Biology 17 (3): 288–99. Mar 2015. doi:10.1038/ncb3114. PMID 25720963. 
  18. ↑ "mTOR-dependent phosphorylation controls TFEB nuclear export". Nature Communications 9 (1): 3312. Aug 2018. doi:10.1038/s41467-018-05862-6. PMID 30120233. Bibcode: 2018NatCo...9.3312N. 
  19. ↑ "A TFEB nuclear export signal integrates amino acid supply and glucose availability". Nature Communications 9 (1): 2685. Jul 2018. doi:10.1038/s41467-018-04849-7. PMID 29992949. Bibcode: 2018NatCo...9.2685L. 
  20. ↑ 20.0 20.1 20.2 "mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases". Nature Communications 8: 14338. Feb 2017. doi:10.1038/ncomms14338. PMID 28165011. Bibcode: 2017NatCo...814338P. 
  21. ↑ "Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency". Autophagy 14 (8): 1419–1434. Jul 2018. doi:10.1080/15548627.2018.1474313. PMID 29916295. 
  22. ↑ "Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes". Nature Immunology 14 (1): 61–71. Jan 2013. doi:10.1038/ni.2475. PMID 23160154. 

Further reading





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