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TFEB
Identifiers
Aliases	TFEB, ALPHABHLHE35, TCFEB, transcription factor EB
External IDs	OMIM: 600744; MGI: 103270; HomoloGene: 5182; GeneCards: TFEB; OMA:TFEB - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6p21.1 Start 41,683,978 bp End 41,736,259 bp
Gene location (Mouse) Chr. Chromosome 17 (mouse) Band 17 C|17 23.99 cM Start 48,047,955 bp End 48,103,344 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in muscle of thigh gastrocnemius muscle apex of heart granulocyte blood C1 segment inferior olivary nucleus spleen inferior ganglion of vagus nerve monocyte Top expressed in muscle of thigh granulocyte esophagus triceps brachii muscle temporal muscle vastus lateralis muscle ankle iris ciliary body gastrocnemius muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding protein dimerization activity DNA-binding transcription factor activity DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm nucleus Biological process autophagy positive regulation of transcription, DNA-templated embryonic placenta development lysosome organization adaptive immune response transcription, DNA-templated positive regulation of autophagy positive regulation of transcription by RNA polymerase II immune system process humoral immune response regulation of transcription, DNA-templated lysosome localization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7942 21425 Ensembl ENSG00000112561 ENSMUSG00000023990 UniProt P19484 Q9R210 RefSeq (mRNA) NM_001167827 NM_001271943 NM_001271944 NM_001271945 NM_007162 NM_001161722 NM_001161723 NM_011549 RefSeq (protein) NP_001161299 NP_001258872 NP_001258873 NP_001258874 NP_009093 NP_001155194 NP_001155195 NP_035679 Location (UCSC) Chr 6: 41.68 – 41.74 Mb Chr 17: 48.05 – 48.1 Mb PubMed search
Wikidata
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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 Ca 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

1. ^ GRCh38: Ensembl release 89: ENSG00000112561 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000023990 – Ensembl, May 2017
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12. 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. PMC 4197862. PMID 25069841.
13. 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. Bibcode:2013PNAS..110E1817D. doi:10.1073/pnas.1305623110. PMC 3651458. PMID 23610405.
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18. Napolitano G, Di Malta C, Esposito A, de Araujo ME, Pece S, Bertalot G, Matarese M, Benedetti V, Zampelli A, Stasyk T, Siciliano D, Venuta A, Cesana M, Vilardo C, Nusco E, Monfregola J, Calcagnì A, Di Fiore PP, Huber LA, Ballabio A (Sep 2020). "A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome". Nature. 585 (7826): 597–602. Bibcode:2020Natur.585..597N. doi:10.1038/s41586-020-2444-0. PMC 7610377. PMID 32612235.
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27. Lotfi P, Tse DY, Di Ronza A, Seymour ML, Martano G, Cooper JD, Pereira FA, Passafaro M, Wu SM, Sardiello M (Jul 2018). "Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency". Autophagy. 14 (8): 1419–1434. doi:10.1080/15548627.2018.1474313. PMC 6103706. PMID 29916295.
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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. doi:10.1242/dev.125.23.4607. 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/mend.14.3.0428. 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. Bibcode:2003PNAS..100.6051D. 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. S2CID 23230901.
• 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. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• 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. S2CID 13515256.

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