TFEB

{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''Transcription factor EB''' is a protein that in humans is encoded by the ''TFEB'' gene.<ref name="pmid2115126">{{cite journal | vauthors = Carr CS, Sharp PA | title = A helix-loop-helix protein related to the immunoglobulin E box-binding proteins | journal = Molecular and Cellular Biology | volume = 10 | issue = 8 | pages = 4384–8 | date = Aug 1990 | pmid = 2115126 | pmc = 360994 | doi = 10.1128/mcb.10.8.4384}}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TFEB transcription factor EB| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7942}}</ref>

== Function ==

TFEB is a master gene for lysosomal biogenesis.<ref name="pmid19556463">{{cite journal | vauthors = 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 | title = A gene network regulating lysosomal biogenesis and function | journal = Science | volume = 325 | issue = 5939 | pages = 473–7 | date = Jul 2009 | pmid = 19556463 | doi = 10.1126/science.1174447 | bibcode = 2009Sci...325..473S | s2cid = 20353685 | doi-access = free }}</ref> It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy.<ref name="pmid19556463"/><ref name="pmid21617040">{{cite journal | vauthors = 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 | title = TFEB links autophagy to lysosomal biogenesis | journal = Science | volume = 332 | issue = 6036 | pages = 1429–33 | date = Jun 2011 | pmid = 21617040 | doi = 10.1126/science.1204592 | pmc=3638014| bibcode = 2011Sci...332.1429S }}</ref> 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.<ref name="pmid19556463"/><ref name="pmid21617040" /> TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy.<ref name="pmid19556463"/><ref name="pmid21617040" /><ref name="pmid21889421">{{cite journal | vauthors = 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 | title = Transcriptional activation of lysosomal exocytosis promotes cellular clearance | journal = Developmental Cell | volume = 21 | issue = 3 | pages = 421–30 | date = Sep 2011 | pmid = 21889421 | doi = 10.1016/j.devcel.2011.07.016 | pmc=3173716}}</ref>

In bacterial infection nicotinic acid adenine dinucleotide phosphate (NAADP) induction of lysosomal Ca²⁺ efflux and TFEB activation leads to enhanced expression of inflammatory cytokines.<ref name="pmid33028824">{{cite journal | vauthors=Xie N, Zhang L, Gao W, Huang C, Zou B | title=NAD + metabolism: pathophysiologic mechanisms and therapeutic potential | journal=Signal Transduction and Targeted Therapy | volume=5 | issue=1 | page=227 | year=2020 | doi = 10.1038/s41392-020-00311-7 | pmc=7539288 | pmid=33028824}}</ref> Viral-mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as Huntington's, Parkinson's, and Alzheimer's diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes.<ref name="pmid19556463"/><ref name="pmid21889421" /><ref name="pmid23604321">{{cite journal | vauthors = 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 | title = TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop | journal = Nature Cell Biology | volume = 15 | issue = 6 | pages = 647–58 | date = Jun 2013 | pmid = 23604321 | pmc = 3699877 | doi = 10.1038/ncb2718 }}</ref><ref>{{cite journal | vauthors = 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 | title = Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB | journal = EMBO Molecular Medicine | volume = 6 | issue = 9 | pages = 1142–60 | date = Sep 2014 | pmid = 25069841 | pmc = 4197862 | doi = 10.15252/emmm.201303671 }}</ref><ref>{{cite journal | vauthors = Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Björklund A | title = TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity | journal = Proc Natl Acad Sci USA | volume = 110 | issue = 19 | pages = 1817–26 | date = May 2013 | pmid = 23610405 | pmc = 3651458 | doi = 10.1073/pnas.1305623110 | bibcode = 2013PNAS..110E1817D | doi-access = free }}</ref> TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington's disease.<ref name="pmid22786682">{{cite journal | vauthors = Tsunemi T, Ashe TD, Morrison BE, Soriano KR, Au J, Roque RA, Lazarowski ER, Damian VA, Masliah E, La Spada AR | title = PGC-1α rescues Huntington's disease proteotoxicity by preventing oxidative stress and promoting TFEB function | journal = Science Translational Medicine | volume = 4 | issue = 142 | pages = 142ra97 | date = Jul 2012 | pmid = 22786682 | doi = 10.1126/scitranslmed.3003799 | pmc = 4096245 }}</ref>

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.<ref name="pmid28619945">{{cite journal | vauthors = 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 | title = Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth | journal = Science | volume = 356 | issue = 6343 | pages = 1188–1192 | date = Jun 2017 | pmid = 28619945 | doi = 10.1126/science.aag2553 | pmc = 5730647 }}</ref><ref name="pmid27668431">{{cite journal | vauthors = 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 | title = Modelling TFE renal cell carcinoma in mice reveals a critical role of WNT signaling | journal = eLife | volume = 5 | date = Sep 2016 | pmid = 27668431 | pmc = 5036965 | doi = 10.7554/eLife.17047 | doi-access = free }}</ref><ref name="pmid26168401">{{cite journal | vauthors = 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| title = Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism| journal = Nature | volume = 524 | issue = 7565 | pages = 361–5 | date = Aug 2015 | pmid = 26168401 | pmc = 5086585| doi = 10.1038/nature14587| bibcode = 2015Natur.524..361P}}</ref>

TFEB constitutive activation, due to FLCN mutations, drives renal cystogenesis and tumorigenesis in Birt–Hogg–Dubé syndrome.<ref name = "Napolitano_2020">{{cite journal |vauthors=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 | title = A substrate-specific mTORC1 pathway underlies Birt–Hogg–Dubé syndrome | journal = Nature | volume = 585 | issue = 7826 | pages = 597–602 | date = Sep 2020 | pmid = 32612235 | doi = 10.1038/s41586-020-2444-0| pmc = 7610377 | bibcode = 2020Natur.585..597N }}</ref>

Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2).<ref name="pmid21617040"/><ref name="pmid22343943">{{cite journal | vauthors = 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 | title = A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB | journal = EMBO Journal | volume = 31 | issue = 5 | pages = 1095–108 | date = Mar 2012 | pmid = 22343943 | pmc = 3298007 | doi = 10.1038/emboj.2012.32 }}</ref><ref name="pmid22576015">{{cite journal | vauthors = Martina JA, Chen Y, Gucek M, Puertollano R | title = MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB | journal = Autophagy | volume = 8 | issue = 6 | pages = 903–14 | date = Jun 2012 | pmid = 22576015 | doi = 10.4161/auto.19653 | pmc=3427256}}</ref><ref name="pmid22692423">{{cite journal | vauthors = Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM | title = The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis | journal = Science Signaling | volume = 5 | issue = 228 | pages = ra42 | date = Jun 2012 | pmid = 22692423 | doi = 10.1126/scisignal.2002790 | pmc=3437338}}</ref>

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.<ref name="pmid22576015" /><ref>{{cite journal | vauthors = Martina JA, Puertollano R | title = RRAG GTPases link nutrient availability to gene expression, autophagy and lysosomal biogenesis | journal = Autophagy | volume = 9 | issue = 6 | pages = 928–30 | date = Jun 2013 | pmid = 23524842 | doi = 10.4161/auto.24371 | pmc=3672304}}</ref><ref name="pmid22692423" /> 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.<ref name="pmid21617040" /> Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin.<ref name="pmid25720963">{{cite journal | vauthors =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| title = Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB | journal = Nature Cell Biology | volume = 17 | issue = 3 | pages = 288–99 | date = Mar 2015 | pmid = 25720963 | doi = 10.1038/ncb3114 | pmc = 4801004 }}</ref>

TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation.<ref name="pmid30120233">{{cite journal | vauthors = Napolitano G, Esposito A, Choi H, Matarese M, Benedetti V, Di Malta C, Monfregola J, Medina DL, Lippincott-Schwartz J, Ballabio A | title = mTOR-dependent phosphorylation controls TFEB nuclear export | journal = Nature Communications | volume = 9 | issue = 1 | page = 3312 | date = Aug 2018 | pmid = 30120233 | pmc = 6098152 | doi = 10.1038/s41467-018-05862-6 | bibcode = 2018NatCo...9.3312N }}</ref><ref>{{cite journal | vauthors = Li L, Friedrichsen HJ, Andrews S, Picaud S, Volpon L, Ngeow K, Berridge G, Fischer R, ((Borden KLB)), Filippakopoulos P, Goding CR | title = A TFEB nuclear export signal integrates amino acid supply and glucose availability | journal = Nature Communications | volume = 9 | issue = 1 | page = 2685 | date = Jul 2018 | pmid = 29992949 | pmc = 6041281 | doi = 10.1038/s41467-018-04849-7| bibcode = 2018NatCo...9.2685L }}</ref>

TFEB is also a target of the protein kinase AKT/PKB.<ref name="Palmieri_2017">{{cite journal | vauthors = 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 | title = mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases | journal = Nature Communications | date = Feb 2017 | pmid = 28165011 | doi = 10.1038/ncomms14338 | volume=8 | pmc=5303831 | article-number=14338| bibcode = 2017NatCo...814338P }}</ref> AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation.<ref name="Palmieri_2017" /> 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.<ref name="Palmieri_2017" /><ref name="pmid29916295">{{cite journal | vauthors = Lotfi P, Tse DY, Di Ronza A, Seymour ML, Martano G, Cooper JD, Pereira FA, Passafaro M, Wu SM, Sardiello M | title = Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency | journal = Autophagy | date = Jul 2018 | volume = 14 | issue = 8 | pages = 1419–1434 | pmid = 29916295 | doi = 10.1080/15548627.2018.1474313| pmc = 6103706 }}</ref>

TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment.<ref name="pmid23160154">{{cite journal | vauthors = Hasan M, Koch J, Rakheja D, Pattnaik AK, Brugarolas J, Dozmorov I, Levine B, Wakeland EK, Lee-Kirsch MA, Yan N | title = Trex1 regulates lysosomal biogenesis and interferon-independent activation of antiviral genes | journal = Nature Immunology | volume = 14 | issue = 1 | pages = 61–71 | date = Jan 2013 | pmid = 23160154 | doi = 10.1038/ni.2475 | pmc = 3522772 }}</ref>

== References == {{reflist}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Steingrímsson E, Sawadogo M, Gilbert DJ, Zervos AS, Brent R, Blanar MA, Fisher DE, Copeland NG, Jenkins NA | title = Murine chromosomal location of five bHLH-Zip transcription factor genes | journal = Genomics | volume = 28 | issue = 2 | pages = 179–83 | date = Jul 1995 | pmid = 8530024 | doi = 10.1006/geno.1995.1129 }} * {{cite journal | vauthors = Steingrímsson E, Tessarollo L, Reid SW, Jenkins NA, Copeland NG | title = The bHLH-Zip transcription factor Tfeb is essential for placental vascularization | journal = Development | volume = 125 | issue = 23 | pages = 4607–16 | date = Dec 1998 | doi = 10.1242/dev.125.23.4607 | pmid = 9806910 | doi-access = free }} * {{cite journal | vauthors = Verastegui C, Bertolotto C, Bille K, Abbe P, Ortonne JP, Ballotti R | title = TFE3, a transcription factor homologous to microphthalmia, is a potential transcriptional activator of tyrosinase and TyrpI genes | journal = Molecular Endocrinology | volume = 14 | issue = 3 | pages = 449–56 | date = Mar 2000 | pmid = 10707962 | doi = 10.1210/mend.14.3.0428 | doi-access = free }} * {{cite journal | vauthors = 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 | title = Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 10 | pages = 6051–6 | date = May 2003 | pmid = 12719541 | pmc = 156324 | doi = 10.1073/pnas.0931430100 | bibcode = 2003PNAS..100.6051D | doi-access = free }} * {{cite journal | vauthors = Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E, Bridge J, Schuuring E, Schoenmakers EF, van Kessel AG | title = Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution | journal = Human Molecular Genetics | volume = 12 | issue = 14 | pages = 1661–9 | date = Jul 2003 | pmid = 12837690 | doi = 10.1093/hmg/ddg178 | doi-access = free }} * {{cite journal | vauthors = Kuiper RP, Schepens M, Thijssen J, Schoenmakers EF, van Kessel AG | title = Regulation of the MiTF/TFE bHLH-LZ transcription factors through restricted spatial expression and alternative splicing of functional domains | journal = Nucleic Acids Research | volume = 32 | issue = 8 | pages = 2315–22 | year = 2004 | pmid = 15118077 | pmc = 419459 | doi = 10.1093/nar/gkh571 }} * {{cite journal | vauthors = 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 | title = 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 | journal = The American Journal of Surgical Pathology | volume = 29 | issue = 2 | pages = 230–40 | date = Feb 2005 | pmid = 15644781 | doi = 10.1097/01.pas.0000146007.54092.37 | s2cid = 23230901 }} * {{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }} * {{cite journal | vauthors = Pecciarini L, Cangi MG, Lo Cunsolo C, Macri' E, Dal Cin E, Martignoni G, Doglioni C | title = Characterization of t(6;11)(p21;q12) in a renal-cell carcinoma of an adult patient | journal = Genes, Chromosomes & Cancer | volume = 46 | issue = 5 | pages = 419–26 | date = May 2007 | pmid = 17285572 | doi = 10.1002/gcc.20422 | s2cid = 13515256 }} {{refend}}