| Structural highlights
Disease
TFEB_HUMAN MiT family translocation renal cell carcinoma.
Function
TFEB_HUMAN Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:30120233, PubMed:31672913, PubMed:35662396). Specifically recognizes and binds E-box sequences (5'-CANNTG-3'); efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF (PubMed:1748288, PubMed:19556463, PubMed:29146937). Involved in the cellular response to amino acid availability by acting downstream of MTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation (PubMed:21617040, PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:35662396). Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423, PubMed:35662396). Specifically recognizes and binds the CLEAR-box sequence (5'-GTCACGTGAC-3') present in the regulatory region of many lysosomal genes, leading to activate their expression, thereby playing a central role in expression of lysosomal genes (PubMed:19556463, PubMed:22692423). Regulates lysosomal positioning in response to nutrient deprivation by promoting the expression of PIP4P1 (PubMed:29146937). Acts as a positive regulator of autophagy by promoting expression of genes involved in autophagy (PubMed:21617040, PubMed:22576015, PubMed:23434374, PubMed:27278822). In association with TFE3, activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4(+) T-cells and thymus-dependent humoral immunity (By similarity). Specifically recognizes the gamma-E3 box, a subset of E-boxes, present in the heavy-chain immunoglobulin enhancer (PubMed:2115126). Plays a role in the signal transduction processes required for normal vascularization of the placenta (By similarity). Involved in the immune response to infection by the bacteria S.aureus, S.typhimurium or S.enterica: infection promotes itaconate production, leading to alkylation, resulting in nuclear localization and transcription factor activity (PubMed:35662396). Itaconate-mediated alkylation activates TFEB-dependent lysosomal biogenesis, facilitating the bacteria clearance during the antibacterial innate immune response (PubMed:35662396).[UniProtKB:Q9R210][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Autophagy supports the fast growth of established tumors and promotes tumor resistance to multiple treatments. Inhibition of autophagy is a promising strategy for tumor therapy. However, effective autophagy inhibitors suitable for clinical use are currently lacking. There is a high demand for identifying novel autophagy drug targets and potent inhibitors with drug-like properties. The transcription factor EB (TFEB) is the central transcriptional regulator of autophagy, which promotes lysosomal biogenesis and functions and systematically up-regulates autophagy. Despite extensive evidence that TFEB is a promising target for autophagy inhibition, no small molecular TFEB inhibitors were reported. Here, we show that an United States Food and Drug Administration (FDA)-approved drug Eltrombopag (EO) binds to the basic helix-loop-helix-leucine zipper domain of TFEB, specifically the bottom surface of helix-loop-helix to clash with DNA recognition, and disrupts TFEB-DNA interaction in vitro and in cellular context. EO selectively inhibits TFEB's transcriptional activity at the genomic scale according to RNA sequencing analyses, blocks autophagy in a dose-dependent manner, and increases the sensitivity of glioblastoma to temozolomide in vivo. Together, this work reveals that TFEB is targetable and presents the first direct TFEB inhibitor EO, a drug compound with great potential to benefit a wide range of cancer therapies by inhibiting autophagy.
A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.,Lin Y, Shi Q, Yang G, Shi F, Zhou Y, Wang T, Xu P, Li P, Liu Z, Sun H, Zhao Z, Ding K, Wang Z, Feng H, Yu B, Fang P, Wang J Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2213670120. doi: , 10.1073/pnas.2213670120. Epub 2023 Feb 7. PMID:36749723[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fisher DE, Carr CS, Parent LA, Sharp PA. TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family. Genes Dev. 1991 Dec;5(12A):2342-52. PMID:1748288 doi:10.1101/gad.5.12a.2342
- ↑ 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. A gene network regulating lysosomal biogenesis and function. Science. 2009 Jul 24;325(5939):473-7. PMID:19556463 doi:10.1126/science.1174447
- ↑ Carr CS, Sharp PA. A helix-loop-helix protein related to the immunoglobulin E box-binding proteins. Mol Cell Biol. 1990 Aug;10(8):4384-8. PMID:2115126 doi:10.1128/mcb.10.8.4384-4388.1990
- ↑ 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. TFEB links autophagy to lysosomal biogenesis. Science. 2011 Jun 17;332(6036):1429-33. PMID:21617040 doi:10.1126/science.1204592
- ↑ 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. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012 Mar 7;31(5):1095-108. PMID:22343943 doi:10.1038/emboj.2012.32
- ↑ Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012 Jun;8(6):903-14. PMID:22576015 doi:10.4161/auto.19653
- ↑ Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, Walther TC, Ferguson SM. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012 Jun 12;5(228):ra42. PMID:22692423 doi:10.1126/scisignal.2002790
- ↑ Chauhan S, Goodwin JG, Chauhan S, Manyam G, Wang J, Kamat AM, Boyd DD. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell. 2013 Apr 11;50(1):16-28. PMID:23434374 doi:10.1016/j.molcel.2013.01.024
- ↑ Bento CF, Ashkenazi A, Jimenez-Sanchez M, Rubinsztein DC. The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat Commun. 2016 Jun 9;7:11803. doi: 10.1038/ncomms11803. PMID:27278822 doi:http://dx.doi.org/10.1038/ncomms11803
- ↑ Willett R, Martina JA, Zewe JP, Wills R, Hammond GRV, Puertollano R. TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes. Nat Commun. 2017 Nov 17;8(1):1580. PMID:29146937 doi:10.1038/s41467-017-01871-z
- ↑ Napolitano G, Esposito A, Choi H, Matarese M, Benedetti V, Di Malta C, Monfregola J, Medina DL, Lippincott-Schwartz J, Ballabio A. mTOR-dependent phosphorylation controls TFEB nuclear export. Nat Commun. 2018 Aug 17;9(1):3312. PMID:30120233 doi:10.1038/s41467-018-05862-6
- ↑ Lawrence RE, Fromm SA, Fu Y, Yokom AL, Kim DJ, Thelen AM, Young LN, Lim CY, Samelson AJ, Hurley JH, Zoncu R. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019 Oct 31. pii: science.aax0364. doi: 10.1126/science.aax0364. PMID:31672913 doi:http://dx.doi.org/10.1126/science.aax0364
- ↑ Zhang Z, Chen C, Yang F, Zeng YX, Sun P, Liu P, Li X. Itaconate is a lysosomal inducer that promotes antibacterial innate immunity. Mol Cell. 2022 Aug 4;82(15):2844-2857.e10. PMID:35662396 doi:10.1016/j.molcel.2022.05.009
- ↑ Lin Y, Shi Q, Yang G, Shi F, Zhou Y, Wang T, Xu P, Li P, Liu Z, Sun H, Zhao Z, Ding K, Wang Z, Feng H, Yu B, Fang P, Wang J. A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2213670120. PMID:36749723 doi:10.1073/pnas.2213670120
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