| 2011 |
TFEB is phosphorylated on serine residues by ERK2 (extracellular signal-regulated kinase 2) under nutrient-replete conditions, which regulates its nuclear localization and activity; starvation reduces ERK2 activity, allowing TFEB nuclear translocation and transcriptional activation of autophagy and lysosomal genes. |
Serine phosphorylation assays, nuclear localization imaging, genetic manipulation of ERK2 activity, gene expression analysis |
Science |
High |
21617040
|
| 2011 |
mTORC1 regulates TFEB phosphorylation and nuclear localization; mTORC1 controls V-ATPase expression through TFEB, linking TFEB to endocytosis regulation. |
Unbiased screen, TFEB phosphorylation assays, nuclear localization imaging, genetic and pharmacological mTORC1 inhibition, endocytosis assays |
The EMBO journal |
High |
21804531
|
| 2012 |
mTORC1 phosphorylates TFEB at Ser211 under normal nutrient conditions, promoting association of TFEB with 14-3-3 (YWHA) family proteins and cytosolic retention; pharmacological or genetic inhibition of mTORC1 causes dissociation of the TFEB/14-3-3 complex and rapid nuclear transport. Active TFEB also associates with late endosomal/lysosomal membranes through interaction with the LAMTOR/RRAG/mTORC1 complex. |
Phosphorylation site mapping (Ser211), Co-IP of TFEB with 14-3-3, pharmacological/genetic mTORC1 inhibition, nuclear localization imaging, lysosomal membrane association assays |
Autophagy |
High |
22576015
|
| 2013 |
During starvation, TFEB drives global transcriptional control of lipid catabolism via Ppargc1α and Pparα and is induced through an autoregulatory feedback loop; viral delivery of TFEB to mouse liver prevented weight gain and metabolic syndrome in obesity models. |
Transcriptome analysis, gene expression studies in starved cells and mice, AAV-mediated TFEB delivery in mouse models of obesity, C. elegans conservation studies |
Nature cell biology |
High |
23604321
|
| 2013 |
TFEB activation enhances folding, trafficking, and lysosomal activity of a destabilized glucocerebrosidase variant (Gaucher disease) and β-hexosaminidase mutant (Tay-Sachs), identifying TFEB as a specific regulator of lysosomal proteostasis through induction of folding chaperones and trafficking machinery. |
TFEB overexpression in cell models, enzymatic activity assays, gene expression profiling of folding/trafficking genes |
Human molecular genetics |
Medium |
23393155
|
| 2015 |
Lysosomal Ca2+ release through mucolipin 1 (MCOLN1/TRPML1) activates the phosphatase calcineurin, which directly binds and dephosphorylates TFEB, promoting its nuclear translocation; genetic and pharmacological inhibition of calcineurin suppresses TFEB activity during starvation and exercise. |
Calcineurin-TFEB binding assays, dephosphorylation assays, genetic calcineurin inhibition, MCOLN1 knockout/pharmacology, nuclear localization imaging in cells and in vivo |
Nature cell biology |
High |
25720963
|
| 2017 |
STUB1, a chaperone-dependent E3 ubiquitin ligase, preferentially targets inactive phosphorylated TFEB for proteasomal degradation; STUB1 deficiency causes accumulation of phosphorylated TFEB with reduced TFEB transcriptional activity and impaired autophagy/mitochondrial biogenesis. |
Co-IP of STUB1 with phosphorylated TFEB, ubiquitination assays, STUB1 knockout mice and cells, proteasome inhibitor experiments, autophagy/mitochondrial biogenesis assays |
The EMBO journal |
High |
28754656
|
| 2017 |
TFEB transcriptionally upregulates TMEM55B, which recruits JIP4 to the lysosomal surface and induces dynein-dependent retrograde lysosomal transport toward microtubule minus-ends; this TFEB/TMEM55B/JIP4 pathway coordinates lysosome positioning in response to starvation and cholesterol-induced stress and is required for autophagosome-lysosome fusion. |
TFEB/TFE3 overexpression and starvation induction, TMEM55B/JIP4 depletion, live-cell imaging of lysosomal positioning, autophagosome-lysosome fusion assays |
Nature communications |
High |
29146937
|
| 2019 |
Spermidine post-translationally modifies the translation factor eIF5A (hypusination), which is essential for the synthesis (translation) of TFEB protein; reduced spermidine in aged B cells leads to reduced TFEB expression and autophagy, and spermidine supplementation restores this pathway. |
Metabolomics, eIF5A hypusination assays, TFEB translation assays, B cell functional studies in aged mice and humans, spermidine supplementation experiments |
Molecular cell |
High |
31474573
|
| 2020 |
CDK4/6 interact with and phosphorylate TFEB and TFE3 in the nucleus, promoting their cytoplasmic export and inactivation; during the cell cycle, reduced CDK4/6 activity (due to cyclin D turnover in S and G2/M phases) allows lysosome biogenesis. |
Co-IP of CDK4/6 with TFEB, in vitro kinase assays, CDK4/6 chemical and genetic inhibition, cell-cycle analysis, lysosome number quantification |
The Journal of cell biology |
High |
32662822
|
| 2020 |
sXBP1 directly occupies the TFEB promoter (−743 to −523 site) and activates TFEB transcription in hepatocytes; hepatic XBP1 deletion suppresses TFEB transcription and autophagy, while sXBP1 overexpression enhances them. |
ChIP analysis of sXBP1 at TFEB promoter, XBP1 liver-specific KO mice, sXBP1 overexpression, TFEB mRNA/protein quantification, autophagy flux assays |
Autophagy |
High |
32597296
|
| 2020 |
PDCD4 suppresses TFEB translation in an eIF4A-dependent manner (requiring both MA3 domains of PDCD4), reducing global TFEB protein levels and lysosomal function, without influencing mTOR- or ERK2-dependent TFEB nucleocytoplasmic shuttling. |
PDCD4 overexpression/knockdown, TFEB translation assays, eIF4A inhibitor experiments, MA3 domain mutants, lysosomal function assays |
Cell death and differentiation |
Medium |
33100324
|
| 2021 |
AMPK directly phosphorylates TFEB on three serine residues (S466, S467, S469), which is required for TFEB transcriptional activity upon nutrient starvation; mTORC1 controls cytosolic retention of TFEB whereas AMPK is essential for its transcriptional activity — these represent distinct regulatory events. |
In vitro AMPK kinase assays on TFEB, phosphorylation site mutagenesis (S466A/S467A/S469A), AMPK inhibition/activation, TFEB target gene expression, FLCN depletion |
Autophagy |
High |
33734022
|
| 2022 |
SIRT1 deacetylates TFEB in response to berberine (via NAD+ synthesis pathway activation), promoting TFEB nuclear translocation and autophagy in peritoneal macrophages. |
Co-IP of SIRT1 with TFEB, acetylation assays, SIRT1 inhibition/activation, nuclear translocation imaging, autophagy assays |
Aging |
Medium |
33639613
|
| 2022 |
TFEB activation, in response to bacterial stimuli, promotes transcription of aconitate decarboxylase (Acod1/Irg1), driving mitochondrial itaconate synthesis; TFEB-driven itaconate is transferred via the Irg1-Rab32-BLOC3 system into the Salmonella-containing vacuole to restrict bacterial survival. |
Cellular imaging, metabolic profiling, TFEB KO macrophages, in vitro and in vivo Salmonella infection models |
Nature metabolism |
High |
35864246
|
| 2022 |
p38 MAPK phosphorylates TFEB at Ser401 within its proline-rich domain in response to oxidative stress, UVC, growth factors, and LPS; this phosphorylation event is required for proper monocyte-to-macrophage differentiation and upregulation of immune genes. |
Phosphorylation site identification (S401), p38 MAPK inhibition/depletion, TFEB-S401A mutant in THP1 cells, differentiation and gene expression assays |
EMBO reports |
High |
36507874
|
| 2022 |
TFEB forms liquid-like condensates via liquid-liquid phase separation (LLPS) with low fusion propensity, maintained by rigid interfacial boundaries; small molecules such as Ro-3306 alter condensate material properties (increasing size and fusion propensity), promoting lysosomal biogenesis and autophagy in a TFEB-dependent manner without altering cytoplasmic-nuclear translocation. |
In vitro droplet reconstitution, force measurement between droplets, interfacial tension/viscosity/elasticity measurements, live-cell imaging of condensates, lysosomal biogenesis assays |
The Journal of cell biology |
High |
35293953
|
| 2022 |
The FACT complex (SSRP1/SUPT16H histone chaperone) physically associates with TFEB in the nucleus upon nutrient deprivation or oxidative stress and is required for efficient induction of lysosomal and antioxidant target genes; FACT depletion impairs TFEB-dependent transcription without affecting TFEB activation, stability, or promoter binding. |
Co-IP of TFEB with FACT components, siRNA depletion of FACT, FACT inhibitor (curaxin) treatment, gene expression analysis of TFEB targets |
Autophagy |
Medium |
35230915
|
| 2022 |
PTEN protein phosphatase activity directly dephosphorylates TFEB at Ser211, facilitating lysosome biogenesis and acidification; PTEN deficiency increases TFEB phosphorylation at Ser211, impairing lysosome biogenesis and increasing exosome secretion. |
In vitro dephosphorylation assays of TFEB by PTEN, loss/gain-of-function of PTEN in CCA cells, lysosome biogenesis assays, exosome secretion quantification, mouse metastasis models |
Gastroenterology |
High |
36436593
|
| 2022 |
BHLHE40 and BHLHE41, transcriptional targets induced by sustained high nuclear TFEB, act in opposition to TFEB at lysosomal cell death target genes, constituting a negative feedback loop in TFEB signaling. |
Genome-wide CRISPR screen, TFEB nuclear localization/stimulation titration, gene expression profiling |
Cell reports |
Medium |
33176151
|
| 2022 |
PIKfyve inhibition selectively impairs mTORC1 access to TFEB (without affecting mTORC1 activity toward S6K1 or other substrates), leading to PP2A-dependent dephosphorylation of TFEB Ser211 and nuclear translocation; calcineurin/PPP3 is not required in this context. |
PIKfyve inhibitor treatment, mTORC1 substrate phosphorylation assays, PP2A and calcineurin inhibition, TFEB Ser211 phosphorylation and nuclear localization assays |
Molecular biology of the cell |
Medium |
35020443
|
| 2022 |
TFEB directly binds CLEAR sites in the ATP7B promoter and first intron in platinum-resistant ovarian cancer cells, accelerating ATP7B transcription and contributing to chemoresistance; TFEB suppression inhibits ATP7B expression and sensitizes cells to cisplatin. |
ChIP of TFEB at ATP7B CLEAR sites, luciferase reporter assays, TFEB knockdown, cisplatin toxicity assays |
Cells |
Medium |
35053335
|
| 2023 |
Cryo-EM structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex reveals that two full Rag-Ragulator complexes present each TFEB molecule to the mTOR active site: one canonical Rag-Ragulator binds Raptor, and a second non-canonical Rag-Ragulator docks onto the first via RagC GDP-dependent contact; the non-canonical Rag dimer binds the first helix of TFEB through a RagC GDP-dependent aspartate clamp. The 108-amino acid TFEB docking domain winds around Raptor and back to RagA. Mutation of the aspartate clamp drives TFEB constitutively into the nucleus without affecting mTORC1 localization. |
Cryo-EM structure determination, in cellulo mutagenesis of aspartate clamp, nuclear localization assays |
Nature |
High |
36697823
|
| 2023 |
PPP1CA (protein phosphatase 1 catalytic subunit alpha) dephosphorylates TFEB and promotes its nuclear translocation; in degenerated nucleus pulposus cells, SUV39H2-mediated K141 mono-methylation of PPP1CA disrupts its interaction with TFEB, blocking TFEB dephosphorylation and nuclear translocation. PPP1R9B facilitates this PPP1CA-TFEB interaction. |
Co-IP of PPP1CA with TFEB, dephosphorylation assays, K141 methylation site identification, SUV39H2 knockdown, nuclear localization and autophagy assays |
Cell death and differentiation |
Medium |
37605006
|
| 2023 |
SMURF1 interacts with both the endolysosomal damage sensor LGALS3 and PPP3CB (calcineurin) to form a LGALS3-SMURF1-PPP3/calcineurin complex on lysosomes; this complex stabilizes TFEB and promotes its nuclear import for lysosomal biogenesis in response to lysosomal damage. SMURF1 acts as a positive regulator of PPP3CB phosphatase activity by promoting dissociation of its autoinhibitory domain. |
Co-IP of SMURF1 with LGALS3 and PPP3CB, SMURF1 knockdown, calcineurin activity assays, TFEB nuclear localization imaging, lysosomal damage models |
Autophagy |
Medium |
37909662
|
| 2023 |
TFEB directly binds the promoter of Sox9 (a biliary/progenitor marker) and drives liver progenitor cell differentiation toward the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation during development and regeneration. |
Genetic interaction studies, ChIP of TFEB at Sox9 promoter, liver-specific TFEB KO and overexpression in mice |
Nature communications |
Medium |
32424153
|
| 2023 |
TFEB transcriptionally upregulates HKDC1 directly (confirmed by ChIP-qPCR); HKDC1 is upregulated under mitochondrial and lysosomal stress in a TFEB-dependent manner. HKDC1 facilitates PINK1 stabilization for mitophagy and interacts with VDACs to maintain mitochondria-lysosome contact and lysosomal repair, independently of its glycolytic function. |
Transcriptome analysis, ChIP-qPCR of TFEB at HKDC1 promoter, HKDC1 KO, PINK1 stabilization assays, mitophagy assays, lysosomal repair assays |
Proceedings of the National Academy of Sciences |
High |
38170752
|
| 2023 |
TFEB directly activates transcription of ERVFRD-1 (a fusogen) in human trophoblasts, promoting syncytiotrophoblast (STB) formation; TFEB deficiency impairs STB differentiation and hormone production; this function is independent of TFEB's canonical role as master regulator of the autophagy-lysosomal pathway. |
TFEB KO mice (systemic and trophoblast-specific), human trophoblast and placenta organoid culture, ChIP of TFEB at ERVFRD-1 promoter, syncytialization and hormone secretion assays |
Proceedings of the National Academy of Sciences |
High |
38968109
|
| 2023 |
TFEB directly binds CLEAR sequences of Atp6v1h (a V-ATPase subunit) to regulate lysosomal acidification; disrupting this TFEB-V-ATPase signaling by mutating the CLEAR sequence of Atp6v1h impairs lysosomal acidification and activity, increases tau pathology, and diminishes microglial immune response in tauopathy. |
Knock-in CLEAR sequence mutant mice crossed with tau transgenic mice, lysosomal acidification assays, single-nucleus RNA-seq, tau pathology analysis |
Nature neuroscience |
High |
37985800
|
| 2024 |
STING activation induces GABARAP lipidation on STING vesicles; membrane-bound GABARAP sequesters the FLCN-FNIP GTPase-activating protein complex, blocking its activity toward RagC/RagD GTPases, thereby abolishing mTORC1-dependent phosphorylation and inactivation of TFEB, leading to TFEB nuclear translocation and lysosome biogenesis. |
STING activation experiments, GABARAP lipidation assays, FLCN-FNIP sequestration assays, Rag GTPase activity assays, TFEB nuclear translocation imaging, lysosomal biogenesis assays |
Immunity |
High |
39689715
|
| 2022 |
SIGMAR1 facilitates TFEB nuclear import by chaperoning the nuclear pore protein POM121, which recruits importin β1 (KPNB1); in C9orf72-ALS cells, hexanucleotide repeat expansion disrupts SIGMAR1-POM121 association and reduces nuclear TFEB. |
Co-IP of SIGMAR1 with POM121 and KPNB1, SIGMAR1/POM121 overexpression, nuclear TFEB quantification, SIGMAR1 agonist (pridopidine) treatment |
Autophagy |
Medium |
35507432
|
| 2022 |
TRIM27 binds to the TFEB promoter and to the transcription factor CREB1, enhancing CREB1-TFEB promoter binding affinity and CREB1 transcriptional activity toward TFEB upon Mycobacterium tuberculosis infection, thereby inducing TFEB expression and autophagy flux. |
ChIP-seq of TRIM27 at TFEB promoter, Co-IP of TRIM27 with CREB1, TRIM27 KO macrophages, electrophoretic mobility shift assay (EMSA), in vitro and in vivo Mtb infection models |
Autophagy |
High |
38390831
|
| 2022 |
TFEB contains a prion-like domain (PrLD) near its N-terminus that mediates co-aggregation with mutant huntingtin (mHTT); TFE3, which lacks this PrLD, does not co-aggregate with mHTT. |
Domain mapping (PrLD deletion mutants), co-aggregation assays in cell models of Huntington disease |
Autophagy |
Medium |
35635192
|
| 2022 |
TFEB activates TGIF1 transcription in epicardial cells; TGIF1 is a TGFβ/Smad pathway repressor, and TFEB overexpression prevents TGFβ-induced EMT in epicardial cells through TGIF1; loss of TFEB sensitizes cells to TGFβ-induced EMT. |
TFEB overexpression/KO in epicardial cells, ChIP of TFEB at Tgif1 promoter, TGFβ treatment, EMT marker assays, in vivo mouse epicardium-specific overexpression |
Nature communications |
Medium |
36057632
|
| 2019 |
TFEB and TFE3 display circadian activation and are responsible for rhythmic induction of autophagy genes during the light phase; TFEB/TFE3 directly regulate Rev-erbα (Nr1d1), a core clock transcriptional repressor, with extensive overlap between TFEB/TFE3 and REV-ERBα cistromes at autophagy and metabolic gene loci. |
Genetic ablation of TFEB/TFE3 in mice, circadian gene expression profiling, ChIP-seq (cistrome analysis), wheel-running behavior assays |
The EMBO journal |
High |
31126958
|
| 2019 |
TFEB promotes expression of endocytic genes and increases cellular endocytosis; TFEB-mediated endocytosis drives assembly of the mTORC1-containing nutrient-sensing complex through formation of endosomes carrying RRAGD, SLC38A9, and AKT, which are required to dissociate TSC2 and re-activate mTORC1 on endolysosomal membranes upon amino acid re-feeding. |
ChIP-seq of TFEB at endocytic gene promoters, endocytosis rate assays, TFEB KO/OE, endosome fractionation, mTORC1 activity assays |
Autophagy |
Medium |
30145926
|
| 2020 |
C9orf72 interacts with and dynamically regulates the levels of Rag GTPases, which are responsible for recruitment of mTOR and TFEB to the lysosome upon amino acid signals; loss of C9orf72 (or its C. elegans ortholog ALFA-1) causes TFEB/HLH-30 nuclear translocation and hyperactivation of lipolysis. |
Co-IP of C9orf72 with Rag GTPases, C9orf72 KO in human cells and ALFA-1 KO in C. elegans, mTOR/TFEB localization assays, lipolysis assays |
PLoS genetics |
Medium |
32282804
|
| 2021 |
FBXO22 ubiquitinates KDM4B complexed with MYC-NCOR1 suppressors for degradation, leading to transcriptional induction of TFEB; mild stress-activated p53 transcriptionally induces FBXO22, which upregulates TFEB and basal autophagy. AKT1-mediated KDM4B phosphorylation blocks FBXO22-mediated ubiquitination, counteracting this pathway. |
ChIP-seq, KDM4B ubiquitination assays, FBXO22 KO mice, FBXO22-overexpressing mice, autophagy flux assays |
Autophagy |
Medium |
33706682
|
| 2022 |
USF2, together with HDAC1, binds the CLEAR motif in lysosomal gene promoters under nutrient-rich conditions, reducing H3K27 acetylation and chromatin accessibility to repress lysosomal gene expression; under starvation, USF2 competes with TFEB for CLEAR motif binding in a phosphorylation-dependent manner (GSK3β phosphorylates USF2 at S155 to govern its DNA-binding activity). |
ChIP of USF2/HDAC1 at CLEAR motifs, histone acetylation assays, chromatin accessibility assays, USF2 S155 phosphorylation site mutants, GSK3β inhibition, competitive binding assays |
Nature communications |
Medium |
39333072
|
| 2024 |
TFEB controls cellular labile iron and prevents ferroptosis through transcriptional upregulation of transferrin receptor 1 (TfR1), increasing TfR1 localization in lysosomes for lysosomal iron import and storage, and upregulating ferritin chains; TfR1 knockdown reverses the iron-protective effects of TFEB overexpression. |
TFEB overexpression, TfR1 knockdown, cellular labile iron measurements, lysosomal TfR1 localization by imaging, ferroptosis assays, ferritin quantification |
Free radical biology & medicine |
Medium |
37683766
|
| 2024 |
TRIM25 promotes K63-polyubiquitination of TFEB, increasing TFEB nuclear translocation and transcription of autophagy-related genes; neddylation of TRIM25 at K117 (by UBC12) reduces steric hindrance in the RING domain, facilitating TRIM25-TFEB ubiquitination activity. |
Co-IP of TRIM25 with TFEB, ubiquitination assays (K63-specific), TRIM25 KO/OE, molecular docking and molecular dynamics simulation of TRIM25 neddylation, nuclear TFEB quantification |
Journal of experimental & clinical cancer research |
Medium |
38926803
|
| 2024 |
TFEB controls syncytiotrophoblast (STB) formation by directly binding to promoters of fusogenic genes (Syncytin-1/Syncytin-2) and CYP19A1 (rate-limiting enzyme for 17β-Estradiol synthesis); TFEB depletion impairs syncytial fusion and reduces placental hormone and E2 secretion. |
ChIP of TFEB at Syncytin/CYP19A1 promoters, TFEB KO in vitro syncytialization models, hormone secretion assays, TFEB rescue experiments |
Cell death and differentiation |
High |
38965447
|
| 2024 |
STING activation leads to TFEB dephosphorylation, nuclear translocation, and lysosomal gene expression through a process requiring STING's proton channel function and the V-ATPase–ATG5–ATG8 cascade; this STING-TFEB axis facilitates lysosomal repair and functions independently of canonical STING immune signaling. |
STING activation in LSD mouse models (Galctwi/twi, Ppt1-/-, Cln7-/-), transcriptomic analysis, immunohistochemistry, snRNA-seq, STING proton channel mutants, TFEB dephosphorylation assays |
Molecular cell |
High |
40185098
|
| 2024 |
HSP90AA1 is phosphorylated by CDK5 at Ser595 under basal conditions; this phosphorylation disrupts HSP90AA1 binding to TFEB and impedes TFEB nuclear localization and autophagy induction; pro-autophagy signaling attenuates CDK5 activity, releasing this inhibition and enabling HSP90AA1-dependent TFEB nuclear localization. |
Co-IP of HSP90AA1 with TFEB, CDK5 phosphorylation of HSP90AA1 at S595, HSP90AA1 inhibition/depletion, nuclear TFEB quantification, C. elegans lifespan assays |
Autophagy |
Medium |
35941759
|
| 2024 |
α-synuclein overexpression reduces mitochondria-lysosome membrane apposition, impairs local Ca2+ transfer between these organelles, and thereby enhances TFEB nuclear translocation; this demonstrates that lysosome-mitochondria contact sites regulate TFEB-mediated signaling via local Ca2+ dynamics. |
SPLICS split-GFP reporter for mitochondria-lysosome contacts, α-synuclein overexpression, Ca2+ transfer measurements, TFEB nuclear localization imaging |
Nature communications |
Medium |
38374070
|
| 2019 |
TFEB drives adipocyte browning and protection from diet-induced metabolic dysfunction through transcriptional upregulation of PGC-1α; adipocyte-specific PGC-1α deletion abrogates the metabolic benefits of TFEB overexpression, demonstrating PGC-1α as the primary downstream effector of TFEB in adipose tissue browning. |
Adipocyte-specific TFEB transgenic mice, adipocyte-specific PGC-1α KO crossed with TFEB transgenic mice, transcriptional profiling, metabolic phenotyping |
Science signaling |
High |
31690633
|
| 2022 |
TFEB undergoes LLPS to form nuclear condensates that regulate target gene transcription; the autophagy-lysosome pathway activity correlates with the material properties (size, fusion propensity) of TFEB condensates. |
In vitro condensate reconstitution, biophysical measurements, live-cell condensate imaging, lysosomal biogenesis assays with small molecules |
The Journal of cell biology |
Medium |
35293953
|