{"gene":"TFEB","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"Serine phosphorylation assays, nuclear localization imaging, genetic manipulation of ERK2 activity, gene expression analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct phosphorylation mapping with functional nuclear localization readout, replicated across multiple studies","pmids":["21617040"],"is_preprint":false},{"year":2011,"finding":"mTORC1 regulates TFEB phosphorylation and nuclear localization; mTORC1 controls V-ATPase expression through TFEB, linking TFEB to endocytosis regulation.","method":"Unbiased screen, TFEB phosphorylation assays, nuclear localization imaging, genetic and pharmacological mTORC1 inhibition, endocytosis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, independently replicated in concurrent papers","pmids":["21804531"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Phosphorylation site mapping (Ser211), Co-IP of TFEB with 14-3-3, pharmacological/genetic mTORC1 inhibition, nuclear localization imaging, lysosomal membrane association assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — specific phosphorylation site identified, binding partner (14-3-3) confirmed by Co-IP, replicated across multiple labs","pmids":["22576015"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Transcriptome analysis, gene expression studies in starved cells and mice, AAV-mediated TFEB delivery in mouse models of obesity, C. elegans conservation studies","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo functional rescue, transcriptomic confirmation, evolutionary conservation demonstrated","pmids":["23604321"],"is_preprint":false},{"year":2013,"finding":"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.","method":"TFEB overexpression in cell models, enzymatic activity assays, gene expression profiling of folding/trafficking genes","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue with defined molecular mechanism, single lab, two disease models","pmids":["23393155"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Calcineurin-TFEB binding assays, dephosphorylation assays, genetic calcineurin inhibition, MCOLN1 knockout/pharmacology, nuclear localization imaging in cells and in vivo","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical dephosphorylation, binding partners confirmed, multiple genetic models in cells and mice, replicated by other labs","pmids":["25720963"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-IP of STUB1 with phosphorylated TFEB, ubiquitination assays, STUB1 knockout mice and cells, proteasome inhibitor experiments, autophagy/mitochondrial biogenesis assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo KO model with defined phenotype","pmids":["28754656"],"is_preprint":false},{"year":2017,"finding":"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.","method":"TFEB/TFE3 overexpression and starvation induction, TMEM55B/JIP4 depletion, live-cell imaging of lysosomal positioning, autophagosome-lysosome fusion assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined molecular pathway with multiple genetic perturbations and functional readouts (lysosome positioning, fusion)","pmids":["29146937"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Metabolomics, eIF5A hypusination assays, TFEB translation assays, B cell functional studies in aged mice and humans, spermidine supplementation experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct translational regulation mechanism established with biochemical and in vivo evidence, multiple orthogonal methods","pmids":["31474573"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-IP of CDK4/6 with TFEB, in vitro kinase assays, CDK4/6 chemical and genetic inhibition, cell-cycle analysis, lysosome number quantification","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — kinase-substrate relationship established biochemically, genetic validation, cell-cycle mechanistic link demonstrated","pmids":["32662822"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ChIP analysis of sXBP1 at TFEB promoter, XBP1 liver-specific KO mice, sXBP1 overexpression, TFEB mRNA/protein quantification, autophagy flux assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence of promoter occupancy, in vivo genetic models, multiple orthogonal methods","pmids":["32597296"],"is_preprint":false},{"year":2020,"finding":"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.","method":"PDCD4 overexpression/knockdown, TFEB translation assays, eIF4A inhibitor experiments, MA3 domain mutants, lysosomal function assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of translational vs. post-translational regulation, domain mutants used, single lab","pmids":["33100324"],"is_preprint":false},{"year":2021,"finding":"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.","method":"In vitro AMPK kinase assays on TFEB, phosphorylation site mutagenesis (S466A/S467A/S469A), AMPK inhibition/activation, TFEB target gene expression, FLCN depletion","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with site-specific mutagenesis, genetic validation, single lab","pmids":["33734022"],"is_preprint":false},{"year":2022,"finding":"SIRT1 deacetylates TFEB in response to berberine (via NAD+ synthesis pathway activation), promoting TFEB nuclear translocation and autophagy in peritoneal macrophages.","method":"Co-IP of SIRT1 with TFEB, acetylation assays, SIRT1 inhibition/activation, nuclear translocation imaging, autophagy assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional assays, pharmacological dissection, single lab","pmids":["33639613"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Cellular imaging, metabolic profiling, TFEB KO macrophages, in vitro and in vivo Salmonella infection models","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Moderate — metabolic profiling + genetic KO + in vivo infection model, multiple orthogonal methods","pmids":["35864246"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Phosphorylation site identification (S401), p38 MAPK inhibition/depletion, TFEB-S401A mutant in THP1 cells, differentiation and gene expression assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — specific phosphorylation site with mutagenesis, kinase identified, functional consequence in differentiation established","pmids":["36507874"],"is_preprint":false},{"year":2022,"finding":"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.","method":"In vitro droplet reconstitution, force measurement between droplets, interfacial tension/viscosity/elasticity measurements, live-cell imaging of condensates, lysosomal biogenesis assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with biophysical characterization, live-cell imaging, functional validation","pmids":["35293953"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP of TFEB with FACT components, siRNA depletion of FACT, FACT inhibitor (curaxin) treatment, gene expression analysis of TFEB targets","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic depletion, pharmacological inhibition, single lab","pmids":["35230915"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro dephosphorylation assay plus in vivo genetic models, site-specific (Ser211)","pmids":["36436593"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Genome-wide CRISPR screen, TFEB nuclear localization/stimulation titration, gene expression profiling","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus transcriptional validation, single lab","pmids":["33176151"],"is_preprint":false},{"year":2022,"finding":"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.","method":"PIKfyve inhibitor treatment, mTORC1 substrate phosphorylation assays, PP2A and calcineurin inhibition, TFEB Ser211 phosphorylation and nuclear localization assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection of kinase/phosphatase specificity, multiple substrates tested, single lab","pmids":["35020443"],"is_preprint":false},{"year":2022,"finding":"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.","method":"ChIP of TFEB at ATP7B CLEAR sites, luciferase reporter assays, TFEB knockdown, cisplatin toxicity assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with functional drug sensitivity readout, single lab","pmids":["35053335"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Cryo-EM structure determination, in cellulo mutagenesis of aspartate clamp, nuclear localization assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis validation in cells, mechanistically comprehensive","pmids":["36697823"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP of PPP1CA with TFEB, dephosphorylation assays, K141 methylation site identification, SUV39H2 knockdown, nuclear localization and autophagy assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical dephosphorylation, Co-IP, methylation site identified, single lab","pmids":["37605006"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-IP of SMURF1 with LGALS3 and PPP3CB, SMURF1 knockdown, calcineurin activity assays, TFEB nuclear localization imaging, lysosomal damage models","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, phosphatase activity assay, genetic knockdown, single lab","pmids":["37909662"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Genetic interaction studies, ChIP of TFEB at Sox9 promoter, liver-specific TFEB KO and overexpression in mice","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed, in vivo genetic models, single lab","pmids":["32424153"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Transcriptome analysis, ChIP-qPCR of TFEB at HKDC1 promoter, HKDC1 KO, PINK1 stabilization assays, mitophagy assays, lysosomal repair assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence, genetic KO, multiple functional readouts, single lab with comprehensive approach","pmids":["38170752"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter ChIP, in vitro and in vivo genetic models, multiple independent TFEB KO approaches, functional hormone assays","pmids":["38968109"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Knock-in CLEAR sequence mutant mice crossed with tau transgenic mice, lysosomal acidification assays, single-nucleus RNA-seq, tau pathology analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in genetic model, mechanistic disruption of specific TFEB-target interaction, multiple functional readouts","pmids":["37985800"],"is_preprint":false},{"year":2024,"finding":"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.","method":"STING activation experiments, GABARAP lipidation assays, FLCN-FNIP sequestration assays, Rag GTPase activity assays, TFEB nuclear translocation imaging, lysosomal biogenesis assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established with multiple biochemical assays, single lab but multiple orthogonal methods","pmids":["39689715"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-IP of SIGMAR1 with POM121 and KPNB1, SIGMAR1/POM121 overexpression, nuclear TFEB quantification, SIGMAR1 agonist (pridopidine) treatment","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex components, pharmacological and genetic rescue, single lab","pmids":["35507432"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, EMSA, Co-IP, genetic KO, multiple orthogonal methods","pmids":["38390831"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Domain mapping (PrLD deletion mutants), co-aggregation assays in cell models of Huntington disease","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutant analysis with biochemical co-aggregation readout, single lab","pmids":["35635192"],"is_preprint":false},{"year":2022,"finding":"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.","method":"TFEB overexpression/KO in epicardial cells, ChIP of TFEB at Tgif1 promoter, TGFβ treatment, EMT marker assays, in vivo mouse epicardium-specific overexpression","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter ChIP, in vivo and in vitro genetic models, single lab","pmids":["36057632"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Genetic ablation of TFEB/TFE3 in mice, circadian gene expression profiling, ChIP-seq (cistrome analysis), wheel-running behavior assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide cistrome analysis, in vivo KO mice with behavioral readout, single lab with multiple orthogonal approaches","pmids":["31126958"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP-seq of TFEB at endocytic gene promoters, endocytosis rate assays, TFEB KO/OE, endosome fractionation, mTORC1 activity assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, functional endocytosis assays, mTORC1 complex assembly readout, single lab","pmids":["30145926"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, cross-species genetic models, functional readout, single lab","pmids":["32282804"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ChIP-seq, KDM4B ubiquitination assays, FBXO22 KO mice, FBXO22-overexpressing mice, autophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and OE mice, ChIP-seq, ubiquitination assays, single lab","pmids":["33706682"],"is_preprint":false},{"year":2022,"finding":"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).","method":"ChIP of USF2/HDAC1 at CLEAR motifs, histone acetylation assays, chromatin accessibility assays, USF2 S155 phosphorylation site mutants, GSK3β inhibition, competitive binding assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, chromatin accessibility, phosphorylation site mutagenesis, single lab","pmids":["39333072"],"is_preprint":false},{"year":2024,"finding":"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.","method":"TFEB overexpression, TfR1 knockdown, cellular labile iron measurements, lysosomal TfR1 localization by imaging, ferroptosis assays, ferritin quantification","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiments, TfR1 dependency established, multiple iron metabolism readouts, single lab","pmids":["37683766"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic manipulation, single lab","pmids":["38926803"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP of TFEB at Syncytin/CYP19A1 promoters, TFEB KO in vitro syncytialization models, hormone secretion assays, TFEB rescue experiments","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter ChIP, multiple KO models, functional hormone secretion assay, replicated in two contemporaneous papers","pmids":["38965447"],"is_preprint":false},{"year":2024,"finding":"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.","method":"STING activation in LSD mouse models (Galctwi/twi, Ppt1-/-, Cln7-/-), transcriptomic analysis, immunohistochemistry, snRNA-seq, STING proton channel mutants, TFEB dephosphorylation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple LSD mouse models, mechanistic dissection of STING proton channel requirement, snRNA-seq, lysosomal repair assay","pmids":["40185098"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-IP of HSP90AA1 with TFEB, CDK5 phosphorylation of HSP90AA1 at S595, HSP90AA1 inhibition/depletion, nuclear TFEB quantification, C. elegans lifespan assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, phosphorylation site identified, genetic depletion, cross-species validation in C. elegans","pmids":["35941759"],"is_preprint":false},{"year":2024,"finding":"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.","method":"SPLICS split-GFP reporter for mitochondria-lysosome contacts, α-synuclein overexpression, Ca2+ transfer measurements, TFEB nuclear localization imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel contact site reporter, functional Ca2+ measurements, genetic manipulation, single lab","pmids":["38374070"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Adipocyte-specific TFEB transgenic mice, adipocyte-specific PGC-1α KO crossed with TFEB transgenic mice, transcriptional profiling, metabolic phenotyping","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistatic genetic interaction in vivo, transcriptional target confirmed, functional rescue experiment","pmids":["31690633"],"is_preprint":false},{"year":2022,"finding":"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.","method":"In vitro condensate reconstitution, biophysical measurements, live-cell condensate imaging, lysosomal biogenesis assays with small molecules","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical characterization, live-cell imaging, single lab","pmids":["35293953"],"is_preprint":false}],"current_model":"TFEB is a bHLH-leucine zipper transcription factor that functions as a master regulator of lysosomal biogenesis, autophagy, and cellular metabolism; its activity is primarily controlled by its subcellular localization, which is determined by multi-site phosphorylation (notably Ser211 by mTORC1 via the Rag-Ragulator megacomplex, Ser401 by p38 MAPK, and S466/467/469 by AMPK) promoting 14-3-3-mediated cytoplasmic retention, while dephosphorylation by calcineurin (activated by lysosomal Ca2+ release via MCOLN1) or PP2A drives nuclear translocation; nuclear TFEB binds CLEAR motifs to activate autophagy, lysosomal, lipid catabolism, and immune defense genes, with additional regulation through ubiquitin-mediated turnover (STUB1 targets phospho-TFEB for proteasomal degradation, TRIM25 K63-ubiquitinates TFEB to promote nuclear entry), translational control (eIF5A hypusination and PDCD4/eIF4A axis), chromatin co-factors (FACT complex), phase separation into nuclear condensates, and non-canonical functions including trophoblast syncytialization (via ERVFRD-1/Syncytins), EMT regulation (via TGIF1), and mitochondrial itaconate synthesis (via Irg1/Acod1)."},"narrative":{"mechanistic_narrative":"TFEB is a basic helix-loop-helix transcription factor that serves as a master regulator of lysosomal biogenesis, autophagy, and cellular catabolic metabolism, binding CLEAR motifs to coordinate lysosomal, autophagic, lipid-catabolic, and metabolic gene programs [PMID:23604321, PMID:37985800]. Its activity is governed predominantly by nucleocytoplasmic shuttling controlled by multi-site phosphorylation: under nutrient-replete conditions mTORC1 phosphorylates TFEB at Ser211, generating a 14-3-3 binding site that retains TFEB in the cytosol, with mTORC1 inhibition triggering rapid nuclear entry [PMID:22576015]. A cryo-EM structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex shows that two Rag-Ragulator complexes present TFEB to mTOR through a RagC-GDP-dependent aspartate clamp, and disrupting this clamp drives TFEB constitutively nuclear [PMID:36697823]. Additional kinases tune this control: ERK2 phosphorylates TFEB under nutrient-replete conditions [PMID:21617040], p38 MAPK phosphorylates Ser401 in response to stress and during macrophage differentiation [PMID:36507874], AMPK phosphorylates S466/S467/S469 to license transcriptional activity distinctly from mTORC1-mediated retention [PMID:33734022], and nuclear CDK4/6 phosphorylation promotes export, linking lysosome biogenesis to the cell cycle [PMID:32662822]. Opposing phosphatases drive nuclear translocation, principally calcineurin activated by MCOLN1-mediated lysosomal Ca2+ release [PMID:25720963], with PP2A [PMID:35020443], PTEN [PMID:36436593], and PPP1CA [PMID:37605006] dephosphorylating Ser211 in distinct contexts. TFEB abundance is further set by ubiquitin-mediated turnover (STUB1 degrades phospho-TFEB [PMID:28754656]; TRIM25 K63-ubiquitinates TFEB to promote nuclear entry [PMID:38926803]) and by translational control through eIF5A hypusination and the PDCD4/eIF4A axis [PMID:31474573, PMID:33100324]. Once nuclear, TFEB partitions into liquid-like condensates whose material properties correlate with downstream autophagy-lysosome output [PMID:35293953] and engages the FACT histone chaperone for efficient target induction [PMID:35230915]. Beyond canonical lysosomal control, TFEB directs lysosome positioning via TMEM55B/JIP4 [PMID:29146937], lipid catabolism and adipose browning via PGC-1α and PPARα [PMID:23604321, PMID:31690633], antimicrobial defense through Acod1/itaconate synthesis [PMID:35864246], iron handling and ferroptosis protection via TfR1 [PMID:37683766], and non-canonical developmental programs including trophoblast syncytialization via Syncytin/ERVFRD-1 [PMID:38968109, PMID:38965447] and EMT control via TGIF1 [PMID:36057632].","teleology":[{"year":2011,"claim":"Established that TFEB activity is gated by signal-responsive phosphorylation rather than constitutive expression, linking nutrient state to its nuclear localization.","evidence":"Serine phosphorylation mapping and nuclear localization imaging with ERK2 manipulation; concurrent unbiased screen tying mTORC1 to TFEB and V-ATPase control","pmids":["21617040","21804531"],"confidence":"High","gaps":["Precise phosphosites and direct kinase contacts not yet resolved","Mechanism of cytosolic retention undefined"]},{"year":2012,"claim":"Identified Ser211 as the mTORC1 phosphosite creating a 14-3-3 docking site, defining the molecular switch for cytosolic retention versus nuclear entry.","evidence":"Ser211 phosphosite mapping, TFEB/14-3-3 Co-IP, mTORC1 inhibition, lysosomal membrane association assays","pmids":["22576015"],"confidence":"High","gaps":["Structural basis of TFEB presentation to mTORC1 not yet known","Phosphatase counteracting Ser211 unidentified"]},{"year":2013,"claim":"Extended TFEB function beyond lysosome biogenesis to global lipid catabolism and whole-body metabolism, showing therapeutic potential in metabolic disease.","evidence":"Transcriptomics, autoregulatory feedback analysis, AAV-TFEB delivery in obese mice, C. elegans conservation; separate work showed TFEB rescues lysosomal proteostasis defects","pmids":["23604321","23393155"],"confidence":"High","gaps":["Direct vs indirect regulation of Ppargc1α/Pparα not fully dissected","Proteostasis effect characterized in single lab"]},{"year":2015,"claim":"Identified the phosphatase arm of the switch, showing lysosomal Ca2+ via MCOLN1 activates calcineurin to dephosphorylate TFEB, closing the lysosome-to-nucleus signaling loop.","evidence":"Calcineurin-TFEB binding and dephosphorylation assays, MCOLN1 genetics, in vivo starvation/exercise models","pmids":["25720963"],"confidence":"High","gaps":["Whether calcineurin is the sole physiological phosphatase unresolved","Site specificity of dephosphorylation not fully mapped"]},{"year":2017,"claim":"Revealed that TFEB output extends to organelle dynamics and protein stability, controlling lysosome positioning and being itself regulated by chaperone-dependent degradation.","evidence":"TMEM55B/JIP4 depletion with live-cell lysosome positioning and fusion assays; STUB1 Co-IP, ubiquitination assays and KO mice","pmids":["29146937","28754656"],"confidence":"High","gaps":["Coordination between positioning and transcriptional programs unclear","Selectivity of STUB1 for phospho-TFEB mechanism partly defined"]},{"year":2019,"claim":"Demonstrated multi-layered control of TFEB abundance and timing through translational regulation, circadian rhythmicity, and tissue-specific metabolic programs.","evidence":"eIF5A hypusination/translation assays in aged B cells; TFEB/TFE3 cistrome and KO mice with circadian readouts; adipocyte-specific TFEB and PGC-1α epistasis","pmids":["31474573","31126958","31690633"],"confidence":"High","gaps":["Interplay between translational and localization control not integrated","Circadian inputs upstream of TFEB undefined"]},{"year":2020,"claim":"Expanded the regulatory network to cell-cycle (CDK4/6), transcriptional induction (sXBP1), and feedback into nutrient sensing via endocytosis.","evidence":"CDK4/6-TFEB kinase assays and cell-cycle analysis; sXBP1 ChIP at TFEB promoter in liver KO mice; ChIP-seq of TFEB at endocytic genes with mTORC1 assembly assays","pmids":["32662822","32597296","30145926"],"confidence":"High","gaps":["Hierarchy among these inputs in vivo unknown","Endocytic feedback role characterized in single lab"]},{"year":2021,"claim":"Separated mTORC1-controlled cytosolic retention from AMPK-controlled transcriptional competence, showing two independent regulatory axes.","evidence":"In vitro AMPK kinase assays, S466A/S467A/S469A mutagenesis, FLCN depletion, target gene expression","pmids":["33734022"],"confidence":"High","gaps":["How AMPK phosphorylation enhances transactivation mechanistically unclear","Integration with localization signals not resolved"]},{"year":2022,"claim":"Resolved nuclear-level regulation (LLPS condensates, FACT cofactor), additional phosphatases/kinases (PP2A, p38, PTEN), and diverse non-canonical outputs in immunity, infection, and differentiation.","evidence":"In vitro condensate reconstitution and biophysics; FACT Co-IP and depletion; PIKfyve/PP2A dissection; p38 S401 mutagenesis; PTEN dephosphorylation and metastasis models; Acod1/itaconate and Salmonella infection models","pmids":["35293953","35230915","35020443","36507874","36436593","35864246"],"confidence":"High","gaps":["Physiological triggers selecting among phosphatases unclear","Functional role of condensate material properties in vivo undefined"]},{"year":2023,"claim":"Defined the structural mechanism of TFEB substrate presentation to mTORC1 and broadened direct target genes into lysosomal repair, neurodegeneration, development, and chemoresistance.","evidence":"Cryo-EM of the mTORC1-TFEB-Rag-Ragulator megacomplex with aspartate clamp mutagenesis; ChIP-defined targets HKDC1, Atp6v1h, Sox9; STING-GABARAP-FLCN axis; SMURF1/PPP1CA/SIGMAR1 regulators","pmids":["36697823","38170752","37985800","32424153","39689715","37909662","37605006"],"confidence":"High","gaps":["Whether the non-canonical Rag dimer mechanism applies to other MiT/TFE members untested","Tissue specificity of newly identified targets unclear"]},{"year":2024,"claim":"Consolidated non-canonical reproductive and metabolic roles and additional layers of ubiquitin and contact-site regulation.","evidence":"ChIP and KO models for Syncytin/CYP19A1 in trophoblast; TfR1-dependent ferroptosis protection; TRIM25 K63-ubiquitination; STING proton-channel-dependent lysosomal repair; mitochondria-lysosome Ca2+ contact regulation","pmids":["38968109","38965447","37683766","38926803","40185098","38374070"],"confidence":"High","gaps":["How canonical and non-canonical TFEB programs are selected in different tissues unknown","Integration of contact-site Ca2+ with calcineurin axis unresolved"]},{"year":null,"claim":"It remains unresolved how the many parallel kinase, phosphatase, ubiquitin, translational, and condensate inputs are integrated into a single quantitative output and how cell type dictates the choice between canonical lysosomal and non-canonical developmental/metabolic programs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of TFEB regulatory integration","Determinants of canonical vs non-canonical gene program selection unknown","Relative in vivo contribution of redundant phosphatases unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,28,27,41,25,26,21,33,45]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[28,21,27,41,25,26,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5,22,16,46]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,9]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,22]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[16,46,17]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,3,5,6,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,45,14,39]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,15,31,42,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,5,22,29]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,7,26,28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,28,34]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[34]}],"complexes":["mTORC1-TFEB-Rag-Ragulator megacomplex","TFEB/14-3-3 complex","TFEB-FACT (SSRP1/SUPT16H) complex"],"partners":["YWHA","RRAG","MTOR","PPP3CB","STUB1","TRIM25","PPP1CA","HSP90AA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19484","full_name":"Transcription factor EB","aliases":["Class E basic helix-loop-helix protein 35","bHLHe35"],"length_aa":476,"mass_kda":52.9,"function":"Transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response (PubMed:21617040, PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:25720963, PubMed:30120233, PubMed:31672913, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823, PubMed:36749723, PubMed:37079666). 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:22343943, PubMed:22576015, PubMed:22692423, PubMed:25720963, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of MTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:25720963, PubMed:32612235, PubMed:32753672, PubMed:35662396, PubMed:36697823). 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). In association with ACSS2, promotes the expression of genes involved in lysosome biogenesis and both autophagy upon glucose deprivation (PubMed:28552616)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P19484/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TFEB","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TFEB","total_profiled":1310},"omim":[{"mim_id":"621550","title":"TRANSMEMBRANE PROTEIN 39A; TMEM39A","url":"https://www.omim.org/entry/621550"},{"mim_id":"620609","title":"LONG-OLSEN-DISTELMAIER SYNDROME; LNGODS","url":"https://www.omim.org/entry/620609"},{"mim_id":"619389","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 29; SCAR29","url":"https://www.omim.org/entry/619389"},{"mim_id":"617221","title":"HEXOKINASE DOMAIN-CONTAINING PROTEIN 1; HKDC1","url":"https://www.omim.org/entry/617221"},{"mim_id":"609096","title":"F-BOX ONLY PROTEIN 22; FBXO22","url":"https://www.omim.org/entry/609096"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":76.5}],"url":"https://www.proteinatlas.org/search/TFEB"},"hgnc":{"alias_symbol":["TCFEB","bHLHe35"],"prev_symbol":[]},"alphafold":{"accession":"P19484","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19484","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19484-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19484-F1-predicted_aligned_error_v6.png","plddt_mean":63.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TFEB","jax_strain_url":"https://www.jax.org/strain/search?query=TFEB"},"sequence":{"accession":"P19484","fasta_url":"https://rest.uniprot.org/uniprotkb/P19484.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19484/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19484"}},"corpus_meta":[{"pmid":"21617040","id":"PMC_21617040","title":"TFEB links autophagy to lysosomal biogenesis.","date":"2011","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21617040","citation_count":2738,"is_preprint":false},{"pmid":"25720963","id":"PMC_25720963","title":"Lysosomal calcium signalling regulates autophagy through calcineurin and ​TFEB.","date":"2015","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25720963","citation_count":1150,"is_preprint":false},{"pmid":"22576015","id":"PMC_22576015","title":"MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB.","date":"2012","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/22576015","citation_count":1113,"is_preprint":false},{"pmid":"23604321","id":"PMC_23604321","title":"TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop.","date":"2013","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23604321","citation_count":848,"is_preprint":false},{"pmid":"27252382","id":"PMC_27252382","title":"TFEB at a glance.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27252382","citation_count":680,"is_preprint":false},{"pmid":"29764979","id":"PMC_29764979","title":"The complex relationship between TFEB transcription factor phosphorylation and subcellular localization.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/29764979","citation_count":433,"is_preprint":false},{"pmid":"21804531","id":"PMC_21804531","title":"Regulation of TFEB and V-ATPases by mTORC1.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21804531","citation_count":392,"is_preprint":false},{"pmid":"27298091","id":"PMC_27298091","title":"TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress.","date":"2016","source":"Annual review of cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27298091","citation_count":353,"is_preprint":false},{"pmid":"26968346","id":"PMC_26968346","title":"The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective.","date":"2016","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/26968346","citation_count":348,"is_preprint":false},{"pmid":"30335591","id":"PMC_30335591","title":"Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30335591","citation_count":338,"is_preprint":false},{"pmid":"31474573","id":"PMC_31474573","title":"Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31474573","citation_count":273,"is_preprint":false},{"pmid":"25048860","id":"PMC_25048860","title":"Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.","date":"2014","source":"Nature reviews. 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assays, nuclear localization imaging, genetic manipulation of ERK2 activity, gene expression analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct phosphorylation mapping with functional nuclear localization readout, replicated across multiple studies\",\n      \"pmids\": [\"21617040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"mTORC1 regulates TFEB phosphorylation and nuclear localization; mTORC1 controls V-ATPase expression through TFEB, linking TFEB to endocytosis regulation.\",\n      \"method\": \"Unbiased screen, TFEB phosphorylation assays, nuclear localization imaging, genetic and pharmacological mTORC1 inhibition, endocytosis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, independently replicated in concurrent papers\",\n      \"pmids\": [\"21804531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation site mapping (Ser211), Co-IP of TFEB with 14-3-3, pharmacological/genetic mTORC1 inhibition, nuclear localization imaging, lysosomal membrane association assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — specific phosphorylation site identified, binding partner (14-3-3) confirmed by Co-IP, replicated across multiple labs\",\n      \"pmids\": [\"22576015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptome analysis, gene expression studies in starved cells and mice, AAV-mediated TFEB delivery in mouse models of obesity, C. elegans conservation studies\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo functional rescue, transcriptomic confirmation, evolutionary conservation demonstrated\",\n      \"pmids\": [\"23604321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"TFEB overexpression in cell models, enzymatic activity assays, gene expression profiling of folding/trafficking genes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue with defined molecular mechanism, single lab, two disease models\",\n      \"pmids\": [\"23393155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Calcineurin-TFEB binding assays, dephosphorylation assays, genetic calcineurin inhibition, MCOLN1 knockout/pharmacology, nuclear localization imaging in cells and in vivo\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical dephosphorylation, binding partners confirmed, multiple genetic models in cells and mice, replicated by other labs\",\n      \"pmids\": [\"25720963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of STUB1 with phosphorylated TFEB, ubiquitination assays, STUB1 knockout mice and cells, proteasome inhibitor experiments, autophagy/mitochondrial biogenesis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo KO model with defined phenotype\",\n      \"pmids\": [\"28754656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"TFEB/TFE3 overexpression and starvation induction, TMEM55B/JIP4 depletion, live-cell imaging of lysosomal positioning, autophagosome-lysosome fusion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined molecular pathway with multiple genetic perturbations and functional readouts (lysosome positioning, fusion)\",\n      \"pmids\": [\"29146937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Metabolomics, eIF5A hypusination assays, TFEB translation assays, B cell functional studies in aged mice and humans, spermidine supplementation experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct translational regulation mechanism established with biochemical and in vivo evidence, multiple orthogonal methods\",\n      \"pmids\": [\"31474573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of CDK4/6 with TFEB, in vitro kinase assays, CDK4/6 chemical and genetic inhibition, cell-cycle analysis, lysosome number quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — kinase-substrate relationship established biochemically, genetic validation, cell-cycle mechanistic link demonstrated\",\n      \"pmids\": [\"32662822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP analysis of sXBP1 at TFEB promoter, XBP1 liver-specific KO mice, sXBP1 overexpression, TFEB mRNA/protein quantification, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence of promoter occupancy, in vivo genetic models, multiple orthogonal methods\",\n      \"pmids\": [\"32597296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"PDCD4 overexpression/knockdown, TFEB translation assays, eIF4A inhibitor experiments, MA3 domain mutants, lysosomal function assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of translational vs. post-translational regulation, domain mutants used, single lab\",\n      \"pmids\": [\"33100324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro AMPK kinase assays on TFEB, phosphorylation site mutagenesis (S466A/S467A/S469A), AMPK inhibition/activation, TFEB target gene expression, FLCN depletion\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with site-specific mutagenesis, genetic validation, single lab\",\n      \"pmids\": [\"33734022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT1 deacetylates TFEB in response to berberine (via NAD+ synthesis pathway activation), promoting TFEB nuclear translocation and autophagy in peritoneal macrophages.\",\n      \"method\": \"Co-IP of SIRT1 with TFEB, acetylation assays, SIRT1 inhibition/activation, nuclear translocation imaging, autophagy assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional assays, pharmacological dissection, single lab\",\n      \"pmids\": [\"33639613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Cellular imaging, metabolic profiling, TFEB KO macrophages, in vitro and in vivo Salmonella infection models\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic profiling + genetic KO + in vivo infection model, multiple orthogonal methods\",\n      \"pmids\": [\"35864246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphorylation site identification (S401), p38 MAPK inhibition/depletion, TFEB-S401A mutant in THP1 cells, differentiation and gene expression assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — specific phosphorylation site with mutagenesis, kinase identified, functional consequence in differentiation established\",\n      \"pmids\": [\"36507874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro droplet reconstitution, force measurement between droplets, interfacial tension/viscosity/elasticity measurements, live-cell imaging of condensates, lysosomal biogenesis assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with biophysical characterization, live-cell imaging, functional validation\",\n      \"pmids\": [\"35293953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of TFEB with FACT components, siRNA depletion of FACT, FACT inhibitor (curaxin) treatment, gene expression analysis of TFEB targets\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic depletion, pharmacological inhibition, single lab\",\n      \"pmids\": [\"35230915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro dephosphorylation assay plus in vivo genetic models, site-specific (Ser211)\",\n      \"pmids\": [\"36436593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide CRISPR screen, TFEB nuclear localization/stimulation titration, gene expression profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus transcriptional validation, single lab\",\n      \"pmids\": [\"33176151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"PIKfyve inhibitor treatment, mTORC1 substrate phosphorylation assays, PP2A and calcineurin inhibition, TFEB Ser211 phosphorylation and nuclear localization assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection of kinase/phosphatase specificity, multiple substrates tested, single lab\",\n      \"pmids\": [\"35020443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP of TFEB at ATP7B CLEAR sites, luciferase reporter assays, TFEB knockdown, cisplatin toxicity assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with functional drug sensitivity readout, single lab\",\n      \"pmids\": [\"35053335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination, in cellulo mutagenesis of aspartate clamp, nuclear localization assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with mutagenesis validation in cells, mechanistically comprehensive\",\n      \"pmids\": [\"36697823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of PPP1CA with TFEB, dephosphorylation assays, K141 methylation site identification, SUV39H2 knockdown, nuclear localization and autophagy assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical dephosphorylation, Co-IP, methylation site identified, single lab\",\n      \"pmids\": [\"37605006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of SMURF1 with LGALS3 and PPP3CB, SMURF1 knockdown, calcineurin activity assays, TFEB nuclear localization imaging, lysosomal damage models\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, phosphatase activity assay, genetic knockdown, single lab\",\n      \"pmids\": [\"37909662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic interaction studies, ChIP of TFEB at Sox9 promoter, liver-specific TFEB KO and overexpression in mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed, in vivo genetic models, single lab\",\n      \"pmids\": [\"32424153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptome analysis, ChIP-qPCR of TFEB at HKDC1 promoter, HKDC1 KO, PINK1 stabilization assays, mitophagy assays, lysosomal repair assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence, genetic KO, multiple functional readouts, single lab with comprehensive approach\",\n      \"pmids\": [\"38170752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter ChIP, in vitro and in vivo genetic models, multiple independent TFEB KO approaches, functional hormone assays\",\n      \"pmids\": [\"38968109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Knock-in CLEAR sequence mutant mice crossed with tau transgenic mice, lysosomal acidification assays, single-nucleus RNA-seq, tau pathology analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in genetic model, mechanistic disruption of specific TFEB-target interaction, multiple functional readouts\",\n      \"pmids\": [\"37985800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"STING activation experiments, GABARAP lipidation assays, FLCN-FNIP sequestration assays, Rag GTPase activity assays, TFEB nuclear translocation imaging, lysosomal biogenesis assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established with multiple biochemical assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39689715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of SIGMAR1 with POM121 and KPNB1, SIGMAR1/POM121 overexpression, nuclear TFEB quantification, SIGMAR1 agonist (pridopidine) treatment\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex components, pharmacological and genetic rescue, single lab\",\n      \"pmids\": [\"35507432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, EMSA, Co-IP, genetic KO, multiple orthogonal methods\",\n      \"pmids\": [\"38390831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Domain mapping (PrLD deletion mutants), co-aggregation assays in cell models of Huntington disease\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutant analysis with biochemical co-aggregation readout, single lab\",\n      \"pmids\": [\"35635192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"TFEB overexpression/KO in epicardial cells, ChIP of TFEB at Tgif1 promoter, TGFβ treatment, EMT marker assays, in vivo mouse epicardium-specific overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter ChIP, in vivo and in vitro genetic models, single lab\",\n      \"pmids\": [\"36057632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic ablation of TFEB/TFE3 in mice, circadian gene expression profiling, ChIP-seq (cistrome analysis), wheel-running behavior assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide cistrome analysis, in vivo KO mice with behavioral readout, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"31126958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq of TFEB at endocytic gene promoters, endocytosis rate assays, TFEB KO/OE, endosome fractionation, mTORC1 activity assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, functional endocytosis assays, mTORC1 complex assembly readout, single lab\",\n      \"pmids\": [\"30145926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, cross-species genetic models, functional readout, single lab\",\n      \"pmids\": [\"32282804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq, KDM4B ubiquitination assays, FBXO22 KO mice, FBXO22-overexpressing mice, autophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and OE mice, ChIP-seq, ubiquitination assays, single lab\",\n      \"pmids\": [\"33706682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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).\",\n      \"method\": \"ChIP of USF2/HDAC1 at CLEAR motifs, histone acetylation assays, chromatin accessibility assays, USF2 S155 phosphorylation site mutants, GSK3β inhibition, competitive binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, chromatin accessibility, phosphorylation site mutagenesis, single lab\",\n      \"pmids\": [\"39333072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"TFEB overexpression, TfR1 knockdown, cellular labile iron measurements, lysosomal TfR1 localization by imaging, ferroptosis assays, ferritin quantification\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiments, TfR1 dependency established, multiple iron metabolism readouts, single lab\",\n      \"pmids\": [\"37683766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic manipulation, single lab\",\n      \"pmids\": [\"38926803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP of TFEB at Syncytin/CYP19A1 promoters, TFEB KO in vitro syncytialization models, hormone secretion assays, TFEB rescue experiments\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter ChIP, multiple KO models, functional hormone secretion assay, replicated in two contemporaneous papers\",\n      \"pmids\": [\"38965447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"STING activation in LSD mouse models (Galctwi/twi, Ppt1-/-, Cln7-/-), transcriptomic analysis, immunohistochemistry, snRNA-seq, STING proton channel mutants, TFEB dephosphorylation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple LSD mouse models, mechanistic dissection of STING proton channel requirement, snRNA-seq, lysosomal repair assay\",\n      \"pmids\": [\"40185098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP of HSP90AA1 with TFEB, CDK5 phosphorylation of HSP90AA1 at S595, HSP90AA1 inhibition/depletion, nuclear TFEB quantification, C. elegans lifespan assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, phosphorylation site identified, genetic depletion, cross-species validation in C. elegans\",\n      \"pmids\": [\"35941759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"SPLICS split-GFP reporter for mitochondria-lysosome contacts, α-synuclein overexpression, Ca2+ transfer measurements, TFEB nuclear localization imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel contact site reporter, functional Ca2+ measurements, genetic manipulation, single lab\",\n      \"pmids\": [\"38374070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Adipocyte-specific TFEB transgenic mice, adipocyte-specific PGC-1α KO crossed with TFEB transgenic mice, transcriptional profiling, metabolic phenotyping\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic genetic interaction in vivo, transcriptional target confirmed, functional rescue experiment\",\n      \"pmids\": [\"31690633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro condensate reconstitution, biophysical measurements, live-cell condensate imaging, lysosomal biogenesis assays with small molecules\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical characterization, live-cell imaging, single lab\",\n      \"pmids\": [\"35293953\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TFEB is a bHLH-leucine zipper transcription factor that functions as a master regulator of lysosomal biogenesis, autophagy, and cellular metabolism; its activity is primarily controlled by its subcellular localization, which is determined by multi-site phosphorylation (notably Ser211 by mTORC1 via the Rag-Ragulator megacomplex, Ser401 by p38 MAPK, and S466/467/469 by AMPK) promoting 14-3-3-mediated cytoplasmic retention, while dephosphorylation by calcineurin (activated by lysosomal Ca2+ release via MCOLN1) or PP2A drives nuclear translocation; nuclear TFEB binds CLEAR motifs to activate autophagy, lysosomal, lipid catabolism, and immune defense genes, with additional regulation through ubiquitin-mediated turnover (STUB1 targets phospho-TFEB for proteasomal degradation, TRIM25 K63-ubiquitinates TFEB to promote nuclear entry), translational control (eIF5A hypusination and PDCD4/eIF4A axis), chromatin co-factors (FACT complex), phase separation into nuclear condensates, and non-canonical functions including trophoblast syncytialization (via ERVFRD-1/Syncytins), EMT regulation (via TGIF1), and mitochondrial itaconate synthesis (via Irg1/Acod1).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TFEB is a basic helix-loop-helix transcription factor that serves as a master regulator of lysosomal biogenesis, autophagy, and cellular catabolic metabolism, binding CLEAR motifs to coordinate lysosomal, autophagic, lipid-catabolic, and metabolic gene programs [#3, #28]. Its activity is governed predominantly by nucleocytoplasmic shuttling controlled by multi-site phosphorylation: under nutrient-replete conditions mTORC1 phosphorylates TFEB at Ser211, generating a 14-3-3 binding site that retains TFEB in the cytosol, with mTORC1 inhibition triggering rapid nuclear entry [#2]. A cryo-EM structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex shows that two Rag-Ragulator complexes present TFEB to mTOR through a RagC-GDP-dependent aspartate clamp, and disrupting this clamp drives TFEB constitutively nuclear [#22]. Additional kinases tune this control: ERK2 phosphorylates TFEB under nutrient-replete conditions [#0], p38 MAPK phosphorylates Ser401 in response to stress and during macrophage differentiation [#15], AMPK phosphorylates S466/S467/S469 to license transcriptional activity distinctly from mTORC1-mediated retention [#12], and nuclear CDK4/6 phosphorylation promotes export, linking lysosome biogenesis to the cell cycle [#9]. Opposing phosphatases drive nuclear translocation, principally calcineurin activated by MCOLN1-mediated lysosomal Ca2+ release [#5], with PP2A [#20], PTEN [#18], and PPP1CA [#23] dephosphorylating Ser211 in distinct contexts. TFEB abundance is further set by ubiquitin-mediated turnover (STUB1 degrades phospho-TFEB [#6]; TRIM25 K63-ubiquitinates TFEB to promote nuclear entry [#40]) and by translational control through eIF5A hypusination and the PDCD4/eIF4A axis [#8, #11]. Once nuclear, TFEB partitions into liquid-like condensates whose material properties correlate with downstream autophagy-lysosome output [#16, #46] and engages the FACT histone chaperone for efficient target induction [#17]. Beyond canonical lysosomal control, TFEB directs lysosome positioning via TMEM55B/JIP4 [#7], lipid catabolism and adipose browning via PGC-1\\u03b1 and PPARα [#3, #45], antimicrobial defense through Acod1/itaconate synthesis [#14], iron handling and ferroptosis protection via TfR1 [#39], and non-canonical developmental programs including trophoblast syncytialization via Syncytin/ERVFRD-1 [#27, #41] and EMT control via TGIF1 [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that TFEB activity is gated by signal-responsive phosphorylation rather than constitutive expression, linking nutrient state to its nuclear localization.\",\n      \"evidence\": \"Serine phosphorylation mapping and nuclear localization imaging with ERK2 manipulation; concurrent unbiased screen tying mTORC1 to TFEB and V-ATPase control\",\n      \"pmids\": [\"21617040\", \"21804531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise phosphosites and direct kinase contacts not yet resolved\", \"Mechanism of cytosolic retention undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Ser211 as the mTORC1 phosphosite creating a 14-3-3 docking site, defining the molecular switch for cytosolic retention versus nuclear entry.\",\n      \"evidence\": \"Ser211 phosphosite mapping, TFEB/14-3-3 Co-IP, mTORC1 inhibition, lysosomal membrane association assays\",\n      \"pmids\": [\"22576015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TFEB presentation to mTORC1 not yet known\", \"Phosphatase counteracting Ser211 unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended TFEB function beyond lysosome biogenesis to global lipid catabolism and whole-body metabolism, showing therapeutic potential in metabolic disease.\",\n      \"evidence\": \"Transcriptomics, autoregulatory feedback analysis, AAV-TFEB delivery in obese mice, C. elegans conservation; separate work showed TFEB rescues lysosomal proteostasis defects\",\n      \"pmids\": [\"23604321\", \"23393155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect regulation of Ppargc1α/Pparα not fully dissected\", \"Proteostasis effect characterized in single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the phosphatase arm of the switch, showing lysosomal Ca2+ via MCOLN1 activates calcineurin to dephosphorylate TFEB, closing the lysosome-to-nucleus signaling loop.\",\n      \"evidence\": \"Calcineurin-TFEB binding and dephosphorylation assays, MCOLN1 genetics, in vivo starvation/exercise models\",\n      \"pmids\": [\"25720963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether calcineurin is the sole physiological phosphatase unresolved\", \"Site specificity of dephosphorylation not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed that TFEB output extends to organelle dynamics and protein stability, controlling lysosome positioning and being itself regulated by chaperone-dependent degradation.\",\n      \"evidence\": \"TMEM55B/JIP4 depletion with live-cell lysosome positioning and fusion assays; STUB1 Co-IP, ubiquitination assays and KO mice\",\n      \"pmids\": [\"29146937\", \"28754656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between positioning and transcriptional programs unclear\", \"Selectivity of STUB1 for phospho-TFEB mechanism partly defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated multi-layered control of TFEB abundance and timing through translational regulation, circadian rhythmicity, and tissue-specific metabolic programs.\",\n      \"evidence\": \"eIF5A hypusination/translation assays in aged B cells; TFEB/TFE3 cistrome and KO mice with circadian readouts; adipocyte-specific TFEB and PGC-1α epistasis\",\n      \"pmids\": [\"31474573\", \"31126958\", \"31690633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between translational and localization control not integrated\", \"Circadian inputs upstream of TFEB undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the regulatory network to cell-cycle (CDK4/6), transcriptional induction (sXBP1), and feedback into nutrient sensing via endocytosis.\",\n      \"evidence\": \"CDK4/6-TFEB kinase assays and cell-cycle analysis; sXBP1 ChIP at TFEB promoter in liver KO mice; ChIP-seq of TFEB at endocytic genes with mTORC1 assembly assays\",\n      \"pmids\": [\"32662822\", \"32597296\", \"30145926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among these inputs in vivo unknown\", \"Endocytic feedback role characterized in single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Separated mTORC1-controlled cytosolic retention from AMPK-controlled transcriptional competence, showing two independent regulatory axes.\",\n      \"evidence\": \"In vitro AMPK kinase assays, S466A/S467A/S469A mutagenesis, FLCN depletion, target gene expression\",\n      \"pmids\": [\"33734022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AMPK phosphorylation enhances transactivation mechanistically unclear\", \"Integration with localization signals not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved nuclear-level regulation (LLPS condensates, FACT cofactor), additional phosphatases/kinases (PP2A, p38, PTEN), and diverse non-canonical outputs in immunity, infection, and differentiation.\",\n      \"evidence\": \"In vitro condensate reconstitution and biophysics; FACT Co-IP and depletion; PIKfyve/PP2A dissection; p38 S401 mutagenesis; PTEN dephosphorylation and metastasis models; Acod1/itaconate and Salmonella infection models\",\n      \"pmids\": [\"35293953\", \"35230915\", \"35020443\", \"36507874\", \"36436593\", \"35864246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological triggers selecting among phosphatases unclear\", \"Functional role of condensate material properties in vivo undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the structural mechanism of TFEB substrate presentation to mTORC1 and broadened direct target genes into lysosomal repair, neurodegeneration, development, and chemoresistance.\",\n      \"evidence\": \"Cryo-EM of the mTORC1-TFEB-Rag-Ragulator megacomplex with aspartate clamp mutagenesis; ChIP-defined targets HKDC1, Atp6v1h, Sox9; STING-GABARAP-FLCN axis; SMURF1/PPP1CA/SIGMAR1 regulators\",\n      \"pmids\": [\"36697823\", \"38170752\", \"37985800\", \"32424153\", \"39689715\", \"37909662\", \"37605006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the non-canonical Rag dimer mechanism applies to other MiT/TFE members untested\", \"Tissue specificity of newly identified targets unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Consolidated non-canonical reproductive and metabolic roles and additional layers of ubiquitin and contact-site regulation.\",\n      \"evidence\": \"ChIP and KO models for Syncytin/CYP19A1 in trophoblast; TfR1-dependent ferroptosis protection; TRIM25 K63-ubiquitination; STING proton-channel-dependent lysosomal repair; mitochondria-lysosome Ca2+ contact regulation\",\n      \"pmids\": [\"38968109\", \"38965447\", \"37683766\", \"38926803\", \"40185098\", \"38374070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How canonical and non-canonical TFEB programs are selected in different tissues unknown\", \"Integration of contact-site Ca2+ with calcineurin axis unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the many parallel kinase, phosphatase, ubiquitin, translational, and condensate inputs are integrated into a single quantitative output and how cell type dictates the choice between canonical lysosomal and non-canonical developmental/metabolic programs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of TFEB regulatory integration\", \"Determinants of canonical vs non-canonical gene program selection unknown\", \"Relative in vivo contribution of redundant phosphatases unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 28, 27, 41, 25, 26, 21, 33, 45]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [28, 21, 27, 41, 25, 26, 33]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [3, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5, 22, 16, 46]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 22]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [16, 46, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 45, 14, 39]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15, 31, 42, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 22, 29]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 7, 26, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 28, 34]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"complexes\": [\n      \"mTORC1-TFEB-Rag-Ragulator megacomplex\",\n      \"TFEB/14-3-3 complex\",\n      \"TFEB-FACT (SSRP1/SUPT16H) complex\"\n    ],\n    \"partners\": [\n      \"YWHA\",\n      \"RRAG\",\n      \"MTOR\",\n      \"PPP3CB\",\n      \"STUB1\",\n      \"TRIM25\",\n      \"PPP1CA\",\n      \"HSP90AA1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}