Affinage

TFE3

Transcription factor E3 · UniProt P19532

Length
575 aa
Mass
61.5 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TFE3 is a basic helix-loop-helix transcription factor that couples nutrient, stress, and cell-cycle signals to the activation of lysosomal, autophagic, and metabolic gene programs through tightly regulated nucleocytoplasmic shuttling (PMID:36608670, PMID:39486419). Under nutrient-replete conditions, amino acids drive Rag-GTPase-dependent recruitment of TFE3 to the lysosomal surface via a conserved alpha-helix that contacts RagA, where an evolutionarily conserved phospho-degron triggers CUL1β-TrCP-mediated ubiquitination and proteasomal degradation; missense mutations at the RagA-TFE3 interface cause a severe neurodevelopmental syndrome, and this phospho-degron is recurrently lost in oncogenic TFE3 translocations (PMID:36608670). mTORC1 enforces cytoplasmic retention, with an autoregulatory feedback in which active mTOR releases from lysosomes to permit TFE3 nuclear accumulation (PMID:39486419), while FLCN promotes mTORC1-dependent phosphorylation as a negative regulator (PMID:36987696). Diverse signals license nuclear entry: AMPK directly phosphorylates three serines required for transcriptional activity upon starvation (PMID:33734022); PERK/eIF2α signaling and calcineurin-mediated dephosphorylation with 14-3-3 dissociation drive translocation during ER and oxidative stress, including TMEM55B-dependent sequestration of FLCN/FNIP at lysosomes (PMID:26813791, PMID:36719671, PMID:38168055); and CDK4/6 and PLK4 phosphorylation restrain nuclear activity to gate lysosome biogenesis with the cell cycle and centrosome status (PMID:32662822, PMID:35316161). In the nucleus, TFE3 requires the FACT histone chaperone complex (SSRP1/SUPT16H) and recruits the H3K27 demethylase KDM6A for efficient transcriptional output, and is destabilized by TRIM28-mediated ubiquitination (PMID:35230915, PMID:36935008). Beyond the CLEAR/autophagy network, TFE3 activates ATF4/UPR genes (PMID:26813791), IRS-2 in hepatic insulin signaling in synergy with Foxo1 (PMID:17279346), Cd40lg in CD4+ T cells (redundantly with TFEB, with double loss causing hyper-IgM syndrome) (PMID:16936731), Rev-erbα in the circadian clock (PMID:31126958), and immune/interferon genes during coronavirus infection (PMID:36785787). Oncogenic chromosomal translocations fuse TFE3 to partners such as ASPSCR1, PRCC, SFPQ, NONO, and WWTR1, bypassing mTORC1/Rag regulation to constitutively localize the fusion to the nucleus and rewire transcription toward OXPHOS, angiogenesis, and mitochondrial programs; ASPSCR1::TFE3 obligately recruits the AAA+ ATPase VCP/p97 to organize enhancer loops driving its oncogenic signature (PMID:38326311, PMID:37029109, PMID:39915638).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    Established that TFE3 has a physiological role beyond lysosomal biology by demonstrating it directly drives CD40 ligand expression in T cells, redundantly with TFEB.

    Evidence T-cell-specific conditional double knockout mice, EMSA/promoter binding, and reporter assays

    PMID:16936731

    Open questions at the time
    • Does not define how TFE3 nuclear activity is regulated in T cells
    • Functional redundancy with TFEB obscures TFE3-specific contributions
  2. 2003 Medium

    Showed that an oncogenic TFE3 fusion can act through mislocalization, with PSF-TFE3 sequestering wild-type TFE3 and p53 in an extranuclear compartment.

    Evidence Subcellular fractionation, immunofluorescence, and siRNA rescue in an endogenous tRCC cell line

    PMID:12902986

    Open questions at the time
    • No structural basis for the abnormal localization
    • Contrasts with later fusions that are constitutively nuclear, indicating fusion-partner-specific behavior
  3. 2007 Medium

    Linked TFE3 to systemic metabolism by identifying IRS-2 as a hepatic target whose activation promotes insulin sensitivity.

    Evidence Promoter reporter and transcriptional interaction studies in hepatic models (review of primary work)

    PMID:17279346

    Open questions at the time
    • Review format limits primary-data resolution
    • Mechanism of Foxo1/SREBP-1c antagonism at the IRS-2 promoter not fully dissected
  4. 2016 High

    Defined a stress-responsive, mTORC1-independent activation route, showing PERK and calcineurin drive TFE3 nuclear entry to upregulate ATF4/UPR genes.

    Evidence Pharmacological PERK/calcineurin inhibition with nuclear translocation and reporter assays

    PMID:26813791

    Open questions at the time
    • Phosphosites controlling ER-stress translocation not mapped
    • Relationship to nutrient-sensing pathway unresolved at this stage
  5. 2016 Medium

    Showed that an oncogenic fusion can paradoxically induce growth arrest, with ASPL-TFE3 transactivating p21 to trigger p53-independent senescence in mesenchymal cells.

    Evidence Ectopic and inducible fusion expression, p21 promoter reporter, senescence assays, and p21 siRNA epistasis

    PMID:27673450

    Open questions at the time
    • Context-dependence of arrest vs transformation unexplained
    • Direct promoter occupancy at endogenous loci not shown
  6. 2018 Medium

    Identified PI3K/AKT/mTOR pathway genes including IRS-1 as direct fusion targets, linking TFE3 translocation RCC to feed-forward growth signaling.

    Evidence TFE3 ChIP-seq in an SFPQ-TFE3 PDX with siRNA knockdown and pathway phospho-readouts

    PMID:30061365

    Open questions at the time
    • Single PDX model
    • Causal contribution of each target to tumor growth not isolated
  7. 2019 High

    Placed TFE3 within circadian and developmental signaling networks via direct regulation of Rev-erbα and as a downstream effector of FLCN suppressing WNT signaling.

    Evidence TFEB/TFE3 double KO mice with ChIP-seq and behavioral assays; FLCN KO with TCF/LEF reporters and TFE3 rescue

    PMID:31126958 PMID:31272105

    Open questions at the time
    • Direct vs indirect mechanism of WNT suppression unclear
    • TFE3-specific cistrome separable from TFEB only partially defined
  8. 2020 Medium

    Revealed cell-cycle and fusion-driven metabolic control: CDK4/6 phosphorylate TFE3 to enforce nuclear export, while PRCC-TFE3 activates PRKN-driven mitophagy and mitochondrial fission programs.

    Evidence Reciprocal Co-IP and CDK4/6 perturbation; promoter/ChIP and mitophagy/ROS assays in PRCC-TFE3 tRCC lines

    PMID:32339358 PMID:32662822 PMID:33019842

    Open questions at the time
    • CDK4/6 phosphosites on TFE3 not mapped
    • Drp1/Fis1 regulation lacks mechanistic dissection (Low confidence)
    • Direct vs indirect fission-gene activation unresolved
  9. 2021 Medium

    Established a dual, opposing kinase logic (AMPK activating, mTORC1 retaining) and identified PLK4 and additional regulators (NRF-1, NUPR1, VPS41/HOPS) controlling TFE3 abundance and localization.

    Evidence In vitro AMPK kinase assays with serine mutants; PLK4 perturbation; NRF-1 ChIP/reporter; NUPR1 proteomics/knockdown; VPS41 patient fibroblasts

    PMID:33734022 PMID:33851776 PMID:34345304 PMID:35316161 PMID:35462576

    Open questions at the time
    • NUPR1-TFE3 direct interaction not established (Low confidence)
    • Whether AMPK and PLK4 act on overlapping or distinct sites unclear
    • Integration of multiple regulators into one kinetic model lacking
  10. 2021 Medium

    Showed convergent enhancer-machinery hijacking and metabolic rewiring by fusions: YAP-TFE3 engages the ATAC HAT complex, and NONO-TFE3 directly activates HIF1A to drive glycolysis and angiogenesis.

    Evidence Co-IP/MS and integrated ChIP-seq/RNA-seq for YAP-TFE3; ChIP and reporter with metabolic assays for NONO-TFE3

    PMID:33845743 PMID:33913810

    Open questions at the time
    • Fusion-partner-specific cofactor requirements not generalized
    • Single cell-line models for metabolic readouts
  11. 2023 High

    Resolved the central nutrient-degradation mechanism: Rag-GTPase recruitment activates a conserved phospho-degron for CUL1β-TrCP-mediated turnover, with disease variants and translocations both disrupting this control.

    Evidence Lysosomal fractionation, ubiquitination assays, RagA Co-IP, degron/helix mutagenesis, and disease-variant validation

    PMID:36608670

    Open questions at the time
    • Kinase generating the degron phosphorylation not fully defined
    • How fusion loss of degron quantitatively elevates nuclear TFE3 not measured
  12. 2023 High

    Defined the nuclear transcriptional machinery and stress inputs: FACT chromatin remodeling and KDM6A recruitment are required for output, TRIM28 limits TFE3 levels, eIF2α phosphorylation and TMEM55B-FLCN/FNIP sequestration gate stress translocation, and FLCN licenses mTORC1-dependent phosphorylation in vivo.

    Evidence Co-IP, siRNA/curaxin, ubiquitination and histone-mark ChIP; phospho-deficient eIF2α cells; TMEM55B KO zebrafish; Flcn/Tfeb/Tfe3 KO mice and xenograft rescue

    PMID:35230915 PMID:36719671 PMID:36935008 PMID:36987696 PMID:38168055

    Open questions at the time
    • Order of FACT vs KDM6A recruitment at target promoters unclear
    • How distinct stress kinases converge on the same translocation machinery not unified
  13. 2023 High

    Showed ASPSCR1::TFE3 governs in vivo tumorigenesis through super-enhancer-driven angiogenesis programs rather than autonomous proliferation.

    Evidence Inducible fusion depletion, H3K27ac ChIP-seq, CRISPR/dCas9 epigenomic screen, and in vivo tumor models

    PMID:37029109

    Open questions at the time
    • Cofactors organizing the super-enhancers not yet identified at this stage
    • In vitro vs in vivo dependence discrepancy mechanistically unexplained
  14. 2024 High

    Identified VCP/p97 as an obligate ASPSCR1::TFE3 cofactor organizing enhancer chromatin, and clarified mTORC1 pool-specific feedback controlling wild-type TFE3 localization.

    Evidence Co-IP/MS, ChIP-seq co-occupancy, HiChIP, VCP ATPase mutants, and in vivo epistasis; activated mTOR mutants with lysosomal fractionation

    PMID:38326311 PMID:39486419

    Open questions at the time
    • Molecular basis of distinct mTORC1 pool substrate specificity unresolved
    • How VCP ATPase activity mechanically organizes enhancer loops not defined
  15. 2024 Medium

    Extended fusion biology to dual transcription/splicing activity and cyclin D1-driven proliferation, and established WWTR1::TFE3 transformation as TEAD-binding-dependent.

    Evidence FRET dimerization, transcriptome/splicing profiling, PDX validation; ChIP-seq and CDK4/6 inhibition; soft agar assay with TEAD-domain mutagenesis

    PMID:38266162 PMID:38380774 PMID:38657118

    Open questions at the time
    • Relative contribution of splicing vs transcription to transformation not quantified
    • WWTR1::TFE3 in vivo relevance from single case
  16. 2025 High

    Defined a TFE3-fusion-selective metabolic vulnerability (OXPHOS dependence and EGLN1) and a role for TFE3 in driving the mesenchymal/invasive melanoma state downstream of MITF-FLCN/FNIP control.

    Evidence Genome-scale CRISPR screen with metabolic flux and EGLN1 inhibition in tRCC; TFE3 deletion and FLCN/FNIP epistasis in MITF-low melanoma

    PMID:39915638 PMID:40138313

    Open questions at the time
    • How the same OXPHOS rewiring generalizes across fusion partners not fully tested
    • Melanoma TFE3 target genes driving invasion not enumerated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the multiple upstream kinases (mTORC1, AMPK, CDK4/6, PLK4, PERK/eIF2α) and phosphatases are integrated into a single quantitative model of TFE3 phosphosite occupancy that dictates localization, stability, and target-gene selectivity.
  • Complete TFE3 phosphosite map across conditions lacking
  • Rules determining which target programs (CLEAR vs UPR vs metabolic) are selected not defined
  • Structural basis of fusion-driven enhancer cofactor recruitment incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 6 GO:0005764 lysosome 3 GO:0005829 cytosol 3 GO:0005768 endosome 1
Pathway
R-HSA-9612973 Autophagy 8 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-4839726 Chromatin organization 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-168256 Immune System 2 R-HSA-9909396 Circadian clock 1
Partners
FLCNFOXO1KDM6ARAGASSRP1SUPT16HTRIM28VCP

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 TFE3 nuclear translocation in response to ER stress requires PERK kinase and calcineurin phosphatase, but is independent of mTORC1. Once nuclear, TFE3 directly transcriptionally upregulates ATF4 and other UPR genes to enhance cellular stress response. Chemical ER stressor treatment, PERK/calcineurin inhibition, nuclear translocation assays, transcriptional reporter assays in mammalian cells The EMBO journal High 26813791
2021 AMPK directly phosphorylates TFE3 on three serine residues (analogous to S466/467/469 in TFEB), which is required for TFE3 transcriptional activity upon nutrient starvation or FLCN depletion. mTORC1 controls TFE3 cytosolic retention, whereas AMPK is specifically required for TFE3 transcriptional activity — a dual and opposing regulatory mechanism. In vitro phosphorylation assays (GST pulldown with AMPK), site-directed mutagenesis (serine-to-alanine mutations), AMPK knockout/pharmacological inhibition, reporter assays in MEFs and cancer cell lines Autophagy High 33734022
2020 CDK4/6 interact with and phosphorylate TFE3 (and TFEB) in the nucleus, promoting their nuclear export and cytoplasmic retention, thereby inactivating lysosome biogenesis programs. During the cell cycle, lysosome numbers increase in S and G2/M phases when cyclin D turnover diminishes CDK4/6 activity. Co-immunoprecipitation, CDK4/6 chemical and genetic inactivation, nuclear/cytoplasmic fractionation, cell-cycle-stage lysosome quantification in mammalian cells The Journal of cell biology High 32662822
2023 Amino acids promote recruitment of TFE3 to the lysosomal surface via Rag GTPases, activating an evolutionarily conserved phospho-degron that leads to ubiquitination by CUL1β-TrCP and proteasomal degradation of TFE3. A conserved alpha-helix in TFE3 is required for interaction with RagA. TFE3 missense mutations within the RagA-TFE3 interface cause a severe neurodevelopmental syndrome. The phospho-degron is recurrently lost in oncogenic TFE3 genomic translocations. Lysosomal fractionation, ubiquitination assays, co-immunoprecipitation with Rag GTPases, mutagenesis of degron and RagA-binding helix, proteasome inhibitor experiments in mammalian cells Molecular cell High 36608670
2006 TFE3 (and TFEB) directly bind to multiple cognate E-box sites in the Cd40lg promoter and are required for maximal CD40 ligand expression in activated CD4+ T cells. Combined T-cell-specific inactivation of TFE3 and TFEB results in hyper-IgM syndrome due to impaired CD40L expression, demonstrating that TFE3 and TFEB are physiologically redundant activators of Cd40lg. T-cell-specific conditional double knockout mice, EMSA/promoter binding assays, promoter-reporter assays, immunological phenotyping Nature immunology High 16936731
2019 TFEB and TFE3 display circadian nuclear activation over the 24-h cycle and directly regulate expression of Rev-erbα (Nr1d1), a core clock repressor. Genetic ablation of TFEB and TFE3 in mice deregulates circadian autophagy gene oscillation and alters circadian wheel-running behavior. ChIP-seq cistrome analysis showed extensive overlap between TFEB/TFE3 and REV-ERBα binding sites at autophagy and metabolic genes. TFEB/TFE3 double knockout mice, ChIP-seq, RNA-seq, circadian behavioral assays The EMBO journal High 31126958
2003 The PSF-TFE3 fusion oncoprotein (arising from SFPQ-TFE3 translocation) localizes to the endosomal compartment rather than the nucleus, unlike wild-type TFE3 or PSF. PSF-TFE3 sequesters wild-type TFE3 and p53 in the extranuclear compartment, rendering them functionally null. siRNA knockdown of PSF-TFE3 in renal carcinoma cells (UOK-145) redistributes endogenous TFE3 and p53 back to the nucleus. Subcellular fractionation, immunofluorescence, siRNA knockdown in endogenous tRCC cell line (UOK-145), co-localization studies Oncogene Medium 12902986
2007 TFE3 strongly activates IRS-2 expression in the liver and regulates hepatic insulin signaling. TFE3 acts in synergy with Foxo1 at the IRS-2 promoter to promote insulin sensitivity, antagonizing SREBP-1c which suppresses IRS-2. TFE3 and SREBP-1c reciprocally regulate IRS-2 expression and insulin sensitivity. Promoter reporter assays, transcriptional activation experiments in hepatic cell models, genetic and biochemical interaction studies (review citing primary experimental work) Journal of molecular medicine Medium 17279346
2019 Loss of FLCN leads to increased nuclear TFE3, which suppresses canonical WNT signaling. Silencing TFE3 in FLCN-deficient cells completely reversed the decreased WNT pathway activity phenotype, placing TFE3 downstream of FLCN and upstream of WNT in lung fibroblasts. Flcn knockout in MEFs and human fetal lung fibroblasts (MRC-5), RNA-seq, TCF/LEF reporter assays, TFE3 siRNA rescue experiments Human molecular genetics Medium 31272105
2021 VPS41 loss of function causes cytosolic redistribution of mTORC1, leading to constitutive nuclear localization of TFE3 and enhanced LC3-II levels, but with a reduced autophagic response to nutrient starvation, demonstrating that HOPS complex-mediated lysosomal function is required for proper mTORC1-dependent TFE3 regulation. Patient fibroblasts with compound heterozygous VPS41 mutations, VPS41 siRNA in HeLa cells, subcellular fractionation, mTORC1 substrate phosphorylation assays EMBO molecular medicine Medium 33851776
2023 TFEB and TFE3 interact with the FACT histone chaperone complex (SSRP1/SUPT16H). This interaction is induced by nuclear translocation of TFEB/TFE3 upon nutrient deprivation or oxidative stress. FACT depletion or inhibition (curaxin) severely impairs induction of antioxidant and lysosomal gene targets without affecting TFEB activation, stability, or promoter binding, demonstrating that FACT chromatin remodeling is required for efficient TFE3 transcriptional output. Co-immunoprecipitation of TFEB/TFE3 with SSRP1/SUPT16H, siRNA depletion of FACT components, curaxin pharmacological inhibition, ChIP assays, gene expression profiling Autophagy Medium 35230915
2023 TRIM28 promotes ubiquitination and proteasome-mediated degradation of TFE3, restraining TFE3-dependent autophagic gene expression in kidney cancer cells. TFE3 interacts with and recruits the histone H3K27 demethylase KDM6A to autophagic gene promoters; KDM6A increases H3K4me3 (rather than demethylating H3K27) at TFE3 target genes to upregulate their expression. Co-immunoprecipitation (TFE3-KDM6A), ubiquitination assays, TRIM28 knockdown/overexpression, histone modification ChIP, proliferation assays in kidney cancer cell lines The Journal of biological chemistry Medium 36935008
2021 Both TFEB and TFE3 are substrates of PLK4 (polo-like kinase 4). Centrosome depletion inactivates PLK4, resulting in TFEB/TFE3 dephosphorylation and nuclear translocation with transcriptional activation of autophagy and lysosome genes, supporting acentrosomal cancer cell proliferation. PLK4 knockout/inhibition, biochemical phosphorylation assays, nuclear translocation imaging, genetic epistasis with TFEB/TFE3 double KO in cancer cells Autophagy Medium 35316161
2023 EIF2S1 (eIF2α) phosphorylation is required for nuclear translocation of TFE3 during ER stress. PPP3/calcineurin-mediated dephosphorylation and YWHA/14-3-3 dissociation are required but insufficient for nuclear retention of TFE3 during ER stress; EIF2AK3/PERK is upstream of this pathway. Overexpression of active ATF6 or XBP1s/ATF4 differentially rescues TFE3 nuclear translocation defects in eIF2α phosphorylation-deficient cells. EIF2S1 phosphorylation-deficient (S51A) cells, nuclear translocation assays, calcineurin and 14-3-3 dissociation experiments, adenoviral overexpression of UPR effectors, autophagy flux assays Autophagy Medium 36719671
2024 mTORC1 restricts TFE3 activity through an auto-regulatory negative feedback: activated mTOR mutants display low lysosome occupancy due to release of mTORC1 from lysosomes dependent on its own kinase activity, causing hypo-phosphorylation and nuclear accumulation of TFE3. Rheb-activated mTORC1 does not increase cytoplasmic/lysosomal mTORC1 ratio, indicating the existence of distinct mTORC1 pools with different substrate specificity toward TFE3. Activated mTOR mutant cell lines, lysosomal fractionation, TFE3 nuclear localization assays, Rheb overexpression experiments in human cells Molecular cell Medium 39486419
2024 TMEM55B sequesters the FLCN/FNIP complex at lysosomes in response to oxidative stress, thereby facilitating TFE3 nuclear translocation and transcriptional activation of stress-response genes. tmem55 knockout zebrafish show increased susceptibility to oxidative stress, confirming in vivo relevance. Co-immunoprecipitation (TMEM55B-FLCN/FNIP), TFE3 nuclear translocation assays, TMEM55B knockout zebrafish model, arsenite stress experiments Nature communications Medium 38168055
2016 The ASPL-TFE3 (ASPSCR1-TFE3) fusion oncoprotein directly activates transcription of p21 (CDKN1A) in a p53-independent manner through binding to the p21 promoter region, causing cell cycle arrest and cellular senescence in mesenchymal stem cells. Ectopic expression of ASPL-TFE3 in 293 cells and tetracycline-inducible mesenchymal stem cells, p21 promoter luciferase reporter, RT-PCR, senescence-associated β-galactosidase assay, p21 siRNA epistasis Neoplasia Medium 27673450
2021 TAZ-CAMTA1 and YAP-TFE3 fusion oncoproteins both interact with YEATS2 and ZZZ3 (components of the ATAC histone acetyltransferase complex) despite dissimilarity of their C-terminal fusion partners. This interaction drives a unique transcriptome by hyperactivating TEAD-based transcription and modulating chromatin via the ATAC complex. Combined proteomic/genetic screen (Co-IP/MS), integrative ChIP-seq and RNA-seq in human and murine cell lines expressing fusion proteins eLife Medium 33913810
2020 PRCC-TFE3 fusion protein, constitutively localized in the nucleus, transcriptionally activates the E3 ubiquitin ligase PRKN/parkin, driving PINK1-PRKN-dependent mitophagy that promotes tRCC cell survival under mitochondrial oxidative damage and cell proliferation by decreasing mitochondrial ROS. PRCC-TFE3 also activates PPARGC1A/PGC1α-NRF1 to accelerate mitochondrial biogenesis. Nuclear localization studies of PRCC-TFE3, ChIP/reporter assays for PRKN promoter, mitophagy flux assays, ROS measurement, proliferation assays in PRCC-TFE3 tRCC cell lines Autophagy Medium 33019842
2020 PRCC-TFE3 fusion positively regulates expression of dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), altering mitochondrial distribution and promoting cell migration and invasion independently of MMP-2/MMP-9 in tRCC cells. PRCC-TFE3 expression in tRCC cell lines, Drp1/Fis1 Western blot and RT-PCR, mitochondrial distribution imaging, migration/invasion assays Cell biology international Low 32339358
2018 TFE3 chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in a SFPQ-TFE3 tRCC patient-derived xenograft showed strong enrichment for PI3K/AKT/mTOR pathway genes as direct transcriptional targets. TFE3 knockdown decreased IRS-1 expression, linking TFE3 to IRS-1/PI3K/mTOR signaling in translocation RCC. TFE3 ChIP-seq in PDX model, TFE3 siRNA knockdown, phospho-S6 and phospho-4EBP1 Western blot Clinical cancer research Medium 30061365
2023 TFEB and TFE3 translocate to the nucleus in response to beta-coronavirus infection via a calcineurin-dependent mechanism, and bind to promoters of multiple lysosomal and immune genes. TFE3/TFEB depletion significantly decreases MHV-induced upregulation of immune regulators, and overexpression of either factor increases cytokine/chemokine expression. TFEB/TFE3 also modulate type I IFN signaling by controlling IRF3 activation. Beta-coronavirus infection of macrophages, TFEB/TFE3 nuclear translocation assays, calcineurin inhibition, TFEB/TFE3 siRNA depletion, promoter ChIP, gene expression analysis iScience Medium 36785787
2021 NUPR1 maintains autophagic flux and lysosomal function by directly increasing TFE3 transcriptional activity. NUPR1 knockdown in OSCC cells reduces TFE3 activity, impairing autophagy and decreasing cancer cell proliferation and metastasis in vitro and in vivo. Quantitative proteomics (TMT-based), NUPR1 stable knockdown, TFE3 activity reporter assays, in vitro and in vivo proliferation/metastasis assays Signal transduction and targeted therapy Low 35462576
2024 ASPSCR1::TFE3 interacts with VCP/p97 (AAA+ ATPase), which co-distributes with the fusion protein across chromatin at enhancers genome-wide. VCP hexameric assembly and enzymatic activity are required for the oncogenic transcriptional signature of ASPSCR1::TFE3, and both proteins are co-dependent for cancer cell proliferation and tumorigenesis in vitro and in mouse models of ASPS and RCC. Co-immunoprecipitation/MS (nuclear complex proteomics), ChIP-seq for ASPSCR1::TFE3 and VCP co-occupancy, HiChIP chromatin conformation, VCP ATPase mutants, in vivo mouse tumor models Nature communications High 38326311
2023 ASPSCR1::TFE3 drives ASPS by regulating transcriptional programs controlling angiogenesis through super-enhancer (SE) modulation. Loss of ASPSCR1::TFE3 expression induces SE redistribution at angiogenesis genes. Epigenomic CRISPR/dCas9 screening identifies Pdgfb, Rab27a, Sytl2, and Vwf as critical angiogenesis targets of ASPSCR1::TFE3 via SE activity. ASPSCR1::TFE3 is dispensable for in vitro tumor maintenance but required for in vivo tumor development via angiogenesis. ASPSCR1::TFE3 inducible expression/depletion, H3K27ac ChIP-seq for SE mapping, CRISPR/dCas9 epigenomic screen, in vivo tumor models Nature communications High 37029109
2024 ASPSCR1::TFE3 directly interacts with key epigenetic regulators at enhancers and promoters. Among effector programs, it drives cyclin D1 expression to support cell proliferation. Disruption of cyclin D1/CDK4 signaling impairs ASPS proliferative capacity. ChIP-seq, transcriptome profiling of ASPS tumors and preclinical models, CDK4/6 inhibitor treatment, CDK4/6 + anti-angiogenesis combination in xenografts Cancer research Medium 38657118
2021 NONO-TFE3 fusion protein directly transcriptionally activates HIF1A expression (confirmed by ChIP and luciferase reporter assay), promoting aerobic glycolysis and angiogenesis under hypoxia in NONO-TFE3 tRCC. ChIP assay, luciferase reporter assay, RT-qPCR, glycolysis/lactate measurements, tube formation and migration assays in UOK109 cells (NONO-TFE3 tRCC) Current cancer drug targets Medium 33845743
2024 TFE3 splicing-factor (TFE3-SF) fusion proteins (e.g., SFPQ-TFE3, NONO-TFE3) drive oncogenic transformation through both transcriptional and RNA splicing activities, differentially altering the transcriptome and splicing landscape in a fusion-partner-dependent manner. Inhibiting TFE3-SF dimerization reverses oncogenic activity. In silico structure prediction, transcriptome and splicing profiling, FRET-based dimerization assay, HTHCS of FDA-approved drug library, 2D/3D PDX validation models Cancer research Medium 38266162
2025 TFE3 gene fusions transcriptionally rewire translocation RCC toward oxidative phosphorylation (OXPHOS), creating dependence on NADH reductive stress management. Genome-scale CRISPR screening identified EGLN1 (PHD2) as a TFE3 fusion-selective vulnerability; EGLN1 inhibition stabilizes HIF-1α and reprograms metabolism away from OXPHOS, suppressing tRCC growth. Genome-scale CRISPR screen, transcriptome profiling, metabolic flux assays (OXPHOS measurement), EGLN1 genetic/pharmacological inhibition in tRCC cell lines and in vivo models Nature metabolism High 39915638
2025 TFE3 drives the mesenchymal/invasive phenotype in melanoma. MITF directly or indirectly activates expression of FNIP1, FNIP2, and FLCN (non-canonical mTORC1 pathway components), which promote cytoplasmic retention and lysosome-mediated degradation of TFE3, thereby suppressing the mesenchymal state. Deletion of TFE3 in MITF-low melanoma cells suppresses migration and metastasis. TFE3 deletion in MITF-low melanoma cell lines, FLCN/FNIP1/FNIP2 overexpression, subcellular fractionation, in vitro migration and in vivo metastasis assays Cell reports Medium 40138313
2023 FLCN acts as a negative regulator of TFE3 (and TFEB) by enabling their phosphorylation by mTORC1. Both Tfeb and Tfe3 contribute in a differential and cooperative manner to kidney cystogenesis in Flcn KO mice. Silencing either TFE3 or TFEB rescues tumorigenesis in human BHD renal tumor cell line-derived xenografts. Flcn/Tfeb/Tfe3 double and triple KO mice, BHD patient-derived tumor analysis, xenograft rescue experiments with TFE3/TFEB silencing EMBO molecular medicine High 36987696
2024 WWTR1::TFE3 fusion protein promotes colony formation in soft agar (oncogenic transformation). The TEAD-binding domain of WWTR1 in the fusion is required for this transformative effect, as mutation of the WWTR1 domain to inhibit TEAD binding abrogates WWTR1::TFE3-driven transformation. Soft agar colony formation assay in NIH3T3 cells, TEAD-binding domain mutagenesis, targeted RNA-seq for fusion identification Genes, chromosomes & cancer Medium 38380774
2021 NRF-1 (Nuclear Respiratory Factor 1) directly binds to the promoter region of TFE3 and transcriptionally activates TFE3 expression. NRF-1 knockdown reduces TFE3 levels, inhibits mTOR pathway activation (phospho-AKT, phospho-S6), blocks cell cycle progression, and reduces mitochondrial biogenesis; TFE3 overexpression rescues these effects. Luciferase promoter reporter assay, ChIP of NRF-1 at TFE3 promoter, shRNA knockdown, TFE3 rescue overexpression, flow cytometry cell cycle analysis in 786-O and 293T cells Oncology letters Medium 34345304

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress. Annual review of cell and developmental biology 353 27298091
2016 TFEB and TFE3 are novel components of the integrated stress response. The EMBO journal 258 26813791
2014 Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nature reviews. Urology 257 25048860
2021 AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3. Autophagy 192 33734022
2021 Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma. Nature communications 121 34489456
2011 Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 111 21602817
2022 NUPR1 promotes the proliferation and metastasis of oral squamous cell carcinoma cells by activating TFE3-dependent autophagy. Signal transduction and targeted therapy 102 35462576
2004 Mitf and Tfe3: members of a b-HLH-ZIP transcription factor family essential for osteoclast development and function. Bone 89 15050900
2020 CDK4/6 regulate lysosome biogenesis through TFEB/TFE3. The Journal of cell biology 88 32662822
2018 Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 78 30061365
2006 Transcription factors TFE3 and TFEB are critical for CD40 ligand expression and thymus-dependent humoral immunity. Nature immunology 76 16936731
2019 NEAT1-TFE3 and KAT6A-TFE3 renal cell carcinomas, new members of MiT family translocation renal cell carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 74 30622287
2019 Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy and metabolism to the peripheral clock. The EMBO journal 66 31126958
2021 YAP1-TFE3-fused hemangioendothelioma: a multi-institutional clinicopathologic study of 24 genetically-confirmed cases. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 59 34381186
2021 TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex. eLife 57 33913810
2024 TFE3 -Rearranged PEComa/PEComa-like Neoplasms : Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy. The American journal of surgical pathology 55 38597260
2021 Uterine PEComas: correlation between melanocytic marker expression and TSC alterations/TFE3 fusions. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 47 34131293
2019 TFEA.ChIP: a tool kit for transcription factor binding site enrichment analysis capitalizing on ChIP-seq datasets. Bioinformatics (Oxford, England) 46 31347689
2021 Recurrent YAP1-TFE3 Gene Fusions in Clear Cell Stromal Tumor of the Lung. The American journal of surgical pathology 45 33899786
2021 Transcription factor enrichment analysis (TFEA) quantifies the activity of multiple transcription factors from a single experiment. Communications biology 44 34079046
2023 TFEB and TFE3 drive kidney cystogenesis and tumorigenesis. EMBO molecular medicine 42 36987696
2021 Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation. EMBO molecular medicine 42 33851776
2023 A central role for regulated protein stability in the control of TFE3 and MITF by nutrients. Molecular cell 41 36608670
2022 Chameleon TFE3-translocation RCC and How Gene Partners Can Change Morphology: Accurate Diagnosis Using Contemporary Modalities. Advances in anatomic pathology 39 35180736
2017 Overexpression of SOX11 and TFE3 in Solid-Pseudopapillary Neoplasms of the Pancreas. American journal of clinical pathology 39 29272888
2019 RBM10-TFE3 renal cell carcinoma characterised by paracentric inversion with consistent closely split signals in break-apart fluorescence in-situ hybridisation: study of 10 cases and a literature review. Histopathology 36 30908700
2019 A novel RBMX-TFE3 gene fusion in a highly aggressive pediatric renal perivascular epithelioid cell tumor. Genes, chromosomes & cancer 35 31408245
2007 SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling. Journal of molecular medicine (Berlin, Germany) 35 17279346
2020 PRCC-TFE3 fusion-mediated PRKN/parkin-dependent mitophagy promotes cell survival and proliferation in PRCC-TFE3 translocation renal cell carcinoma. Autophagy 34 33019842
2021 Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey. Journal of clinical pathology 33 33514585
2016 Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements. Oncotarget 33 26840265
2023 The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis. Proceedings of the National Academy of Sciences of the United States of America 32 37216554
2022 TFE3 and TFEB-rearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms. Virchows Archiv : an international journal of pathology 32 35980471
2023 Phosphorylation of EIF2S1 (eukaryotic translation initiation factor 2 subunit alpha) is indispensable for nuclear translocation of TFEB and TFE3 during ER stress. Autophagy 31 36719671
2024 Corynoxine promotes TFEB/TFE3-mediated autophagy and alleviates Aβ pathology in Alzheimer's disease models. Acta pharmacologica Sinica 30 38225393
2021 Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway. Cell death & disease 30 33637706
2003 PSF-TFE3 oncoprotein in papillary renal cell carcinoma inactivates TFE3 and p53 through cytoplasmic sequestration. Oncogene 30 12902986
2022 PEComa-like Neoplasms Characterized by ASPSCR1-TFE3 Fusion: Another Face of TFE3-related Mesenchymal Neoplasia. The American journal of surgical pathology 28 35848761
2016 Renal cell carcinoma with TFE3 translocation and succinate dehydrogenase B mutation. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 28 27910947
2023 ASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma. Nature communications 27 37029109
2016 ASPL-TFE3 Oncoprotein Regulates Cell Cycle Progression and Induces Cellular Senescence by Up-Regulating p21. Neoplasia (New York, N.Y.) 27 27673450
2022 The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity. Redox biology 25 35313207
2023 TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy. The Journal of biological chemistry 24 36935008
2023 Lessons from 801 clinical TFE3/TFEB fluorescence in situ hybridization assays performed on renal cell carcinoma suspicious for MiTF family aberrations. American journal of clinical pathology 24 37499055
2021 Translation Inhibitors Activate Autophagy Master Regulators TFEB and TFE3. International journal of molecular sciences 24 34769510
2022 The FACT complex facilitates expression of lysosomal and antioxidant genes through binding to TFEB and TFE3. Autophagy 23 35230915
2020 Transcription factor EB and TFE3: new metabolic coordinators mediating adaptive responses to exercise in skeletal muscle? American journal of physiology. Endocrinology and metabolism 23 32830550
2024 TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress. Nature communications 22 38168055
2023 TNEA therapy promotes the autophagic degradation of NLRP3 inflammasome in a transgenic mouse model of Alzheimer's disease via TFEB/TFE3 activation. Journal of neuroinflammation 22 36732771
2022 TFEB- and TFE3-dependent autophagy activation supports cancer proliferation in the absence of centrosomes. Autophagy 22 35316161
2020 TFE3 Gene Rearrangement in Perivascular Epithelioid Cell Neoplasm (PEComa) of the Genitourinary Tract. Clinical genitourinary cancer 20 32576448
2023 Emerging roles of TFE3 in metabolic regulation. Cell death discovery 19 36906611
2019 Loss of FLCN inhibits canonical WNT signaling via TFE3. Human molecular genetics 19 31272105
2019 Hepatic YAP1-TFE3 Rearranged Epithelioid Hemangioendothelioma. Case reports in gastrointestinal medicine 17 31341686
2025 Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma. Nature metabolism 16 39915638
2024 TFE3-rearranged nonmelanotic renal PEComa: a case series expanding their phenotypic and fusion landscape. Histopathology 16 39169706
2022 Multiparameter phenotypic screening for endogenous TFEB and TFE3 translocation identifies novel chemical series modulating lysosome function. Autophagy 16 35786165
2024 Patients with ASPSCR1-TFE3 fusion achieve better response to ICI based combination therapy among TFE3-rearranged renal cell carcinoma. Molecular cancer 15 38926757
2020 Ocular PEComas are frequently melanotic and TFE3-translocated: report of two cases including the first description of PRCC-TFE3 fusion in PEComa. Virchows Archiv : an international journal of pathology 15 32676967
2025 Evaluation of 3,606 renal cell tumors for TFE3 rearrangements and TFEB alterations via fluorescence in situ hybridization, next generation sequencing, and GPNMB immunohistochemistry. Human pathology 14 40381702
2024 TFE3-Rearranged Tumors of the Kidney: An Emerging Conundrum. Cancers 14 39410016
2024 mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes. Molecular cell 14 39486419
2018 TFE3-Expressing Perivascular Epithelioid Cell Tumor of the Breast. Journal of pathology and translational medicine 14 30269476
2020 TFE3-PD-L1 axis is pivotal for sunitinib resistance in clear cell renal cell carcinoma. Journal of cellular and molecular medicine 13 33145941
2016 Hypoxia induces TFE3 expression in head and neck squamous cell carcinoma. Oncotarget 13 26872381
2024 Epithelioid hemangioendothelioma (EHE) with WWTR1::TFE3 gene fusion, a novel fusion variant. Genes, chromosomes & cancer 12 38380774
2024 Renal epithelioid angiomyolipomas overexpress TFE3 and the TFE3-regulated gene TRIM63 in the absence of TFE3 rearrangement. Virchows Archiv : an international journal of pathology 12 38971946
2024 Integrated stress response plasticity governs normal cell adaptation to chronic stress via the PP2A-TFE3-ATF4 pathway. Cell death and differentiation 12 39349971
2024 TFE3 -rearranged Head and Neck Neoplasms : Twenty-two Cases Spanning the Morphologic Continuum Between Alveolar Soft Part Sarcoma and PEComa and Highlighting Genotypic Diversity. The American journal of surgical pathology 12 39593216
2023 Beta-coronaviruses exploit cellular stress responses by modulating TFEB and TFE3 activity. iScience 12 36785787
2023 Molecular Characterization of TFE3-Rearranged Renal Cell Carcinoma: A Comparative Study With Papillary and Clear Cell Renal Cell Carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 12 38104891
2022 TFE3 Rearrangement and Expression in Renal Cell Carcinoma. International journal of surgical pathology 12 35912477
2024 Comprehensive molecular characterization of TFE3-rearranged renal cell carcinoma. Experimental & molecular medicine 11 39085357
2021 NRF-1 directly regulates TFE3 and promotes the proliferation of renal cancer cells. Oncology letters 11 34345304
2021 A YAP1::TFE3 cutaneous low-grade fibromyxoid neoplasm: A novel entity! Genes, chromosomes & cancer 11 34874592
2025 TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling. Autophagy 10 40195022
2024 ASPSCR1::TFE3 Drives Alveolar Soft Part Sarcoma by Inducing Targetable Transcriptional Programs. Cancer research 10 38657118
2023 TFE3-immunopositive papillary renal cell carcinoma: A clinicopathological, immunohistochemical, and genetic study. Pathology, research and practice 10 36669395
2023 Novel NONO::TFE3 fusion and ALK co-expression identified in a subset of cutaneous microcystic/reticular schwannoma. Virchows Archiv : an international journal of pathology 10 37468653
2021 TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson's Disease. Frontiers in cell and developmental biology 10 34912803
2020 PRCC-TFE3 regulates migration and invasion of translocation renal cell carcinomas via activation of Drp1-dependent mitochondrial fission. Cell biology international 10 32339358
2019 TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome. American journal of medical genetics. Part A 10 31833172
2013 Establishment of an ASPL-TFE3 renal cell carcinoma cell line (S-TFE). Cancer biology & therapy 10 23760492
2025 SFPQ::TFE3-rearranged PEComa: Differences and analogies with renal cell carcinoma carrying the same translocation. Pathology, research and practice 9 40239600
2024 TFE3-Splicing Factor Fusions Represent Functional Drivers and Druggable Targets in Translocation Renal Cell Carcinoma. Cancer research 9 38266162
2024 TFEB and TFE3 cooperate in regulating inorganic arsenic-induced autophagy-lysosome impairment and immuno-dysfunction in primary dendritic cells. Cell biology and toxicology 9 38267572
2023 LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner. Journal of experimental & clinical cancer research : CR 9 37770905
2019 Nuclear TFE3 expression is a diagnostic marker for Desmoid-type fibromatosis. Diagnostic pathology 9 31043173
2025 Isowalsuranolide targets TrxR1/2 and triggers lysosomal biogenesis and autophagy via the p53-TFEB/TFE3 axis. Science China. Life sciences 8 40059270
2025 Antagonistic roles for MITF and TFE3 in melanoma plasticity. Cell reports 8 40138313
2024 ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97. Nature communications 8 38326311
2024 Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation. Skeletal muscle 8 38643162
2021 NONO-TFE3 Fusion Promotes Aerobic Glycolysis and Angiogenesis by Targeting HIF1A in NONO-TFE3 Translocation Renal Cell Carcinoma. Current cancer drug targets 8 33845743
2021 Orbital TFE3-Rearranged Perivascular Epithelioid Cell Tumor: A Case Report and Review of the Literature. The American Journal of dermatopathology 8 34291749
2018 Adult-onset renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion: 3 case reports and review of literature. Medicine 8 29901594
2017 TFE3 regulates renal adenocarcinoma cell proliferation via activation of the mTOR pathway. Molecular medicine reports 8 28713889
2024 TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment. The American journal of pathology 7 38588851
2023 TFE3-mediated impairment of lysosomal biogenesis and defective autophagy contribute to fluoride-induced hepatotoxicity. Ecotoxicology and environmental safety 7 36827899
2023 Neratinib is a TFEB and TFE3 activator that potentiates autophagy and unbalances energy metabolism in ERBB2+ breast cancer cells. Biochemical pharmacology 7 37269887
2019 A renal cell carcinoma with EWSR1-TFE3 fusion gene. Genes, chromosomes & cancer 7 31774608

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