TFEB

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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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 a mouse model of Juvenile Batten disease.[20] TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.[21]

References

  1. ↑ Carr CS, Sharp PA (Aug 1990). "A helix-loop-helix protein related to the immunoglobulin E box-binding proteins". Molecular and Cellular Biology. 10 (8): 4384–8. doi:10.1128/mcb.10.8.4384. PMC 360994. PMID 2115126.
  2. ↑ "Entrez Gene: TFEB transcription factor EB".
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS, Banfi S, Parenti G, Cattaneo E, Ballabio A (Jul 2009). "A gene network regulating lysosomal biogenesis and function". Science. 325 (5939): 473–7. doi:10.1126/science.1174447. PMID 19556463.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A (Jun 2011). "TFEB links autophagy to lysosomal biogenesis". Science. 332 (6036): 1429–33. doi:10.1126/science.1204592. PMC 3638014. PMID 21617040.
  5. ↑ 5.0 5.1 Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C, Puri C, Pignata A, Martina JA, Sardiello M, Palmieri M, Polishchuk R, Puertollano R, Ballabio A (Sep 2011). "Transcriptional activation of lysosomal exocytosis promotes cellular clearance". Developmental Cell. 21 (3): 421–30. doi:10.1016/j.devcel.2011.07.016. PMC 3173716. PMID 21889421.
  6. ↑ Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, Huynh T, Carissimo A, Palmer D, Klisch TJ, Wollenberg AC, Di Bernardo D, Chan L, Irazoqui JE, Ballabio A (Jun 2013). "TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop". Nature Cell Biology. 15 (6): 647–58. doi:10.1038/ncb2718. PMID 23604321.
  7. ↑ Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, Swartzlander DB, Palmieri M, di Ronza A, Lee VM, Sardiello M, Ballabio A, Zheng H (Sep 2014). "Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB". EMBO Molecular Medicine. 6 (9): 1142–60. doi:10.15252/emmm.201303671. PMID 25069841.
  8. ↑ Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A (May 2013). "TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity". Proc Natl Acad Sci USA. 110 (19): 1817–26. doi:10.1073/pnas.1305623110. PMID 23610405.
  9. ↑ Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E, La Spada AR (Jul 2012). "PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function". Science Translational Medicine. 4 (142): 142ra97. doi:10.1126/scitranslmed.3003799. PMC 4096245. PMID 22786682.
  10. ↑ Di Malta C, Siciliano D, Calcagni A, Monfregola J, Punzi S, Pastore N, Eastes AN, Davis O, De Cegli R, Zampelli A, Di Giovannantonio LG, Nusco E, Platt N, Guida A, Ogmundsdottir MH, Lanfrancone L, Perera RM, Zoncu R, Pelicci PG, Settembre C, Ballabio A (Jun 2017). "Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth". Science. 356 (6343): 1188–1192. doi:10.1126/science.aag2553. PMC 5730647. PMID 28619945.
  11. ↑ Calcagnì A, Kors L, Verschuren E, De Cegli R, Zampelli N, Nusco E, Confalonieri S, Bertalot G, Pece S, Settembre C, Malouf GG, Leemans JC, de Heer E, Salvatore M, Peters DJ, Di Fiore PP, Ballabio A (Sep 2016). "Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling". Elife. 5. doi:10.7554/eLife.17047. PMID 27668431.
  12. ↑ Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N (Aug 2015). "Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism". Nature. 524 (7565): 361–5. doi:10.1038/nature14587. PMID 26168401.
  13. ↑ Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V, Sabatini DM, Ballabio A (Mar 2012). "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB". EMBO Journal. 31 (5): 1095–108. doi:10.1038/emboj.2012.32. PMID 22343943.
  14. ↑ 14.0 14.1 Martina JA, Chen Y, Gucek M, Puertollano R (Jun 2012). "MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB". Autophagy. 8 (6): 903–14. doi:10.4161/auto.19653. PMC 3427256. PMID 22576015.
  15. ↑ 15.0 15.1 Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM (Jun 2012). "The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis". Science Signaling. 5 (228): ra42. doi:10.1126/scisignal.2002790. PMC 3437338. PMID 22692423.
  16. ↑ Martina JA, Puertollano R (Jun 2013). "RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis". Autophagy. 9 (6): 928–30. doi:10.4161/auto.24371. PMC 3672304. PMID 23524842.
  17. ↑ Medina DL, Di Paola S, Peluso I, Armani A, De Stefani D, Venditti R, Montefusco S, Scotto-Rosato A, Prezioso C, Forrester A, Settembre C, Wang W, Gao Q, Xu H, Sandri M, Rizzuto R, De Matteis MA, Ballabio A (Mar 2015). "Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB". Nature Cell Biology. 17 (3): 288–99. doi:10.1038/ncb3114. PMC 4801004. PMID 25720963.
  18. ↑ Napolitano G, Esposito A, Choi H, Matarese M, Benedetti V, Di Malta C, Monfregola J, Medina DL, Lippincott-Schwartz J, Ballabio A (Aug 2018). "mTOR-dependent phosphorylation controls TFEB nuclear export". Nature Communications. 9 (1). doi:10.1038/s41467-018-05862-6. PMID 30120233.
  19. ↑ Li L, Friedrichsen HJ, Andrews S, Picaud S, Volpon L, Ngeow K, Berridge G, Fischer R, Borden KLB, Filippakopoulos P, Goding CR (Jul 2018). "A TFEB nuclear export signal integrates amino acid supply and glucose availability". Nature Communications. 9 (1). doi:10.1038/s41467-018-04849-7. PMID 29992949.
  20. ↑ 20.0 20.1 20.2 Palmieri M, Pal R, Nelvagal HR, Lotfi P, Stinnett GR, Seymour ML, Chaudhury A, Bajaj L, Bondar VV, Bremner L, Saleem U, Tse DY, Sanagasetti D, Wu SM, Neilson JR, Pereira FA, Pautler RG, Rodney GG, Cooper JD, Sardiello M (Feb 2017). "mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases". Nature Communications. 8: 14338. doi:10.1038/ncomms14338. PMC 5303831. PMID 28165011.
  21. ↑ Hasan M, Koch J, Rakheja D, Pattnaik AK, Brugarolas J, Dozmorov I, Levine B, Wakeland EK, Lee-Kirsch MA, Yan N (Jan 2013). "Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes". Nature Immunology. 14 (1): 61–71. doi:10.1038/ni.2475. PMC 3522772. PMID 23160154.

Further reading

  • Steingrímsson E, Sawadogo M, Gilbert DJ, Zervos AS, Brent R, Blanar MA, Fisher DE, Copeland NG, Jenkins NA (Jul 1995). "Murine chromosomal location of five bHLH-Zip transcription factor genes". Genomics. 28 (2): 179–83. doi:10.1006/geno.1995.1129. PMID 8530024.
  • Steingrímsson E, Tessarollo L, Reid SW, Jenkins NA, Copeland NG (Dec 1998). "The bHLH-Zip transcription factor Tfeb is essential for placental vascularization". Development. 125 (23): 4607–16. PMID 9806910.
  • Verastegui C, Bertolotto C, Bille K, Abbe P, Ortonne JP, Ballotti R (Mar 2000). "TFE3, a transcription factor homologous to microphthalmia, is a potential transcriptional activator of tyrosinase and TyrpI genes". Molecular Endocrinology. 14 (3): 449–56. doi:10.1210/me.14.3.449. PMID 10707962.
  • Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez-Atayde AR, Argani P, Ladanyi M, Fletcher JA, Fisher DE (May 2003). "Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation". Proceedings of the National Academy of Sciences of the United States of America. 100 (10): 6051–6. doi:10.1073/pnas.0931430100. PMC 156324. PMID 12719541.
  • Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E, Bridge J, Schuuring E, Schoenmakers EF, van Kessel AG (Jul 2003). "Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution". Human Molecular Genetics. 12 (14): 1661–9. doi:10.1093/hmg/ddg178. PMID 12837690.
  • Kuiper RP, Schepens M, Thijssen J, Schoenmakers EF, van Kessel AG (2004). "Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains". Nucleic Acids Research. 32 (8): 2315–22. doi:10.1093/nar/gkh571. PMC 419459. PMID 15118077.
  • Argani P, Laé M, Hutchinson B, Reuter VE, Collins MH, Perentesis J, Tomaszewski JE, Brooks JS, Acs G, Bridge JA, Vargas SO, Davis IJ, Fisher DE, Ladanyi M (Feb 2005). "Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR". The American Journal of Surgical Pathology. 29 (2): 230–40. doi:10.1097/01.pas.0000146007.54092.37. PMID 15644781.
  • Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
  • Pecciarini L, Cangi MG, Lo Cunsolo C, Macri' E, Dal Cin E, Martignoni G, Doglioni C (May 2007). "Characterization of t(6;11)(p21;q12) in a renal-cell carcinoma of an adult patient". Genes, Chromosomes & Cancer. 46 (5): 419–26. doi:10.1002/gcc.20422. PMID 17285572.


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