TFEB
Master transcription factor for lysosome biogenesis and autophagy. mTORC1 phosphorylates TFEB to trap it in the cytosol; when mTORC1 is off, TFEB enters the nucleus and turns on the cell's recycling program.
The master switch for recycling genes. The master control switch for making new lysosomes and ramping up cellular cleanup. mTORC1 normally keeps it locked out of the nucleus; once mTORC1 turns off, it moves in and switches on the cell's recycling genes.
Phosphorylated on S211 in a Rag- and FLCN-dependent, substrate-selective manner; this is the clearest case where mTORC1 substrate choice – not overall activity – is the regulated variable.
TL;DR. TFEB appears in 17 curated studies in Oliver's mTOR Atlas: 5 in animal models; 11 at the molecular level (cells, biochemistry, structure); 1 review. No study in people is recorded for it in the Atlas yet. It has 3 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| TFEB activates Autophagy mechanism: transcriptional · this link in full · on the map table | Once inside the nucleus, TFEB switches on a whole set of genes for cleanup and for building new lysosomes. Holds under: Human and mouse cell studies (SET2011, ROC2012, SET2012). The gene programme is shown in cells; its contribution to autophagy in living tissue and in people is not measured here. Same flux caveat as ULK1-AUTOPHAGY: TFEB target-gene induction (more lysosomes, more autophagy machinery transcribed) is not itself proof that degradative flux increased - it raises capacity, which still needs to be confirmed with a flux readout rather than assumed from expression alone. plausible in people, not shown directly · settled in the literature | M | SET2011, ROC2012, SET2012 |
| TFEB activates Lysosomal biogenesis mechanism: transcriptional · this link in full · on the map table | In the nucleus, TFEB switches on a whole gene package for cleanup and for building new lysosomes. Holds under: Transcriptional output measured as gene expression and lysosomal markers; how much the compartment actually expands varies with cell type and starvation depth. plausible in people, not shown directly · settled in the literature | M | SET2011, ROC2012, SAR2009, PEN2011 |
| mTORC1 inhibits TFEB mechanism: phosphorylation · this link in full · on the map table | Active mTORC1 tags TFEB and traps it outside the nucleus; switch mTORC1 off and TFEB moves in. Holds under: RagD specifically (more than RagC) promotes TFEB/TFE3 phosphorylation via tighter LAMTOR binding — GOL2022 shows this is paralogue-specific, not a generic Rag-dimer property. Substrate-selective. Depends on FLCN/FNIP RagC/D status, so mTORC1 can be active on S6K1 while not phosphorylating TFEB. plausible in people, not shown directly · settled in the literature | M | ROC2012, SET2012, MAR2012, SET2011, GOL2022, CUI2023, MAR2013 conflicting: ZHANG2026, PEN2011 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 5 |
| M | Molecular — cells, biochemistry, structure | 11 |
| R | Review — secondary literature, not a new result | 1 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | Astragaloside IV Mitigates Tacrolimus-Induced Chronic Nephrotoxicity by Regulating the mTOR-TFEB-GADD45α Pathway. GAO2026 Astragaloside IV protects against tacrolimus-induced nephrotoxicity by inhibiting mTOR to activate TFEB and restore autophagy, nominating the mTOR-TFEB-GADD45alpha axis as a calcineurin-independent candidate therapeutic target (preclinical; no human data) in TICN. |
| 2026 | A | Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma. ZHANG2026 TSC1 loss drives non-canonical mTORC1-mediated TFEB nuclear translocation, promoting hepatocyte-to-biliary plasticity and spontaneous aggressive HCC in mice; Tsc1/Tfeb double knockout rescues the phenotype. |
| 2026 | A | mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation ZAU2026 Establishes a new mTORC1-TFEB/TFE3 signaling axis controlling hepatic bile acid metabolism. Depending on mTORC1 signaling state, mice show coordinated shifts in bile-acid species (non-12-OH vs 12-OH) via altered enzyme expression and cholesterol trafficking; these shifts are reversed by mTORC1 pathway deletion or rapamycin treatment. Dietary protein restriction (which inhibits mTORC1) produces a similar bile-acid shift in mice and correlates with improved metabolic outcomes in human MASLD patients, linking mTORC1 nutrient sensing directly to bile-acid homeostasis and fatty liver disease. |
| 2026 | A | Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis FER2026 Using kidney-specific mouse models that genetically uncouple mTORC1 activity from TFEB/TFE3 activity (Depdc5-KO, RagC-KO, and Flcn/RagC double-KO), the authors show mTORC1 hyperactivation -- not TFEB/TFE3 activation alone -- is the primary driver of kidney cystogenesis and tumorigenesis in Birt-Hogg-Dube and Tuberous Sclerosis Complex models. Constitutive TFEB/TFE3 activity further accelerates disease on top of mTORC1-driven pathology. |
| 2013 | A | TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop SET2013 The authors found that fasting switches on the TFEB gene in mouse liver, muscle and kidney, and that TFEB drives its own transcription by binding CLEAR sites in its promoter, an autoregulatory loop that starvation strengthens. Liver TFEB overexpression changed 773 genes up and 611 down, with lipid catabolism as the top category, and acted largely through PGC-1alpha and PPARalpha: 74% of TFEB-induced genes failed to rise in mice lacking PPARalpha. Mice lacking liver TFEB built up liver fat and mobilised fat poorly during fasting and gained more weight on a high-fat diet, while liver TFEB overexpression prevented and halted diet-induced obesity and improved glucose tolerance in obese ob/ob mice; the lipid effect required autophagy (lost in Atg7-deleted liver). In C. elegans, the TFEB homologue HLH-30 was needed for lipid mobilisation and survival during starvation. Boundary: Mice and worms, with TFEB delivered by virus at overexpression levels. mTORC1 was not manipulated or measured; its role is inferred from earlier work. Not tested in people. |
| 2026 | M | FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer ULL2026 In BHD patient-derived kidney cancer cells, FLCN loss causes constitutive nuclear TFEB localization and mTORC1 hyperactivation, but leaves bulk autophagy flux and LC3 lipidation unaffected; however, the autophagy receptor SQSTM1/p62 accumulates in enlarged puncta, a finding replicated in a Norwegian cohort of BHD patient kidney tumors, showing p62 accumulation is dissociable from bulk autophagic flux. |
| 2026 | M | A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation. ESP2026 Identifies a nutrient-independent lysosomal pathway in which v-ATPase recruits TBK1/ULK1 to phosphorylate FNIP1, inhibiting the FLCN:FNIP complex and releasing TFEB for nuclear translocation; recurrent ATP6V1B2 mutations found in follicular lymphoma patients constitutively hyperactivate this axis, driving TFEB-dependent tumor proliferation. |
| 2026 | M | Structure and function of TM6SF1 reveals role in mTORC1 signaling HON2026 Cryo-EM structure of TM6SF1 identifies it as a lysosomal cholesterol-binding protein that directly engages LAMTOR1 (Ragulator) to regulate mTORC1 signaling in a cholesterol-dependent manner. |
| 2026 | R | Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome CAO2026 Reframes Birt-Hogg-Dube (BHD) syndrome beyond the classic 'global mTORC1 hyperactivation' model: FLCN acts as a GAP for RagC/D, giving substrate-selective (not global) mTORC1 control. Biallelic FLCN loss drives kidney tumors via MiT/TFE nuclear accumulation, while haploinsufficiency alone is sufficient for lung and skin lesions -- resolving the 'mTORC1 paradox' via gene dosage and signaling timing. Narrative synthesis of human genetics and mouse mechanistic data. |
| 2023 | M | Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex CUI2023 First structural view of how mTORC1 actually reaches TFEB to phosphorylate it: two full Rag-Ragulator complexes present a single TFEB molecule to the mTOR active site, one in the normal Raptor-docking arrangement and a second, non-canonical one that grips TFEB's own first helix. Mutating that grip point drives TFEB straight into the nucleus (turning on autophagy/lysosome genes) without disturbing where mTORC1 itself sits. Explains, at the level of atoms, why TFEB phosphorylation needs the tumour suppressor FLCN and the GDP-loaded state of RagC in a way the authors report for no other mTORC1 substrate. Boundary: cryo-EM of a complex reconstituted from purified human proteins — a static structural snapshot, not a live cell or a real-time measurement. |
| 2023 | M | Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis SPA2023 Live imaging of single MCF10A cells shows mTORC1-TFEB signalling adjusts continuously to amino acids and insulin, given alone, one after another or together; at physiological amino acid levels TFEB, AMPK and AKT activity fluctuate in step, and these graded changes track protein synthesis rate through a distributed set of mTORC1 effectors. |
| 2022 | M | A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids GOL2022 The four mammalian Rag GTPase paralogues are not functionally interchangeable: RagC/D determines substrate specificity (RagD favors TFEB/TFE3 phosphorylation via tighter LAMTOR binding), while RagA/B determines the response to amino acid withdrawal (RagB-expressing cells keep mTORC1 lysosomal and active even upon starvation). Author correction issued 2023 (PMID 36536178, no change to conclusions). |
| 2013 | M | Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes MAR2013 The authors asked how TFEB reaches the lysosome, where mTORC1 phosphorylates it. In human cells, depleting Raptor inactivated mTORC1 and sent TFEB to the nucleus but did not stop TFEB binding lysosomes (82.5% of cells still showed lysosomal TFEB), whereas depleting the Rag GTPases or the Ragulator subunit p18 abolished it (under 4% of Rag-depleted cells kept the S211A mutant on lysosomes, against about 80% of controls). TFEB bound only active Rag heterodimers through its first 30 amino acids, and active Rags were enough to bring TFEB to lysosomes; TFEB mutants that could not bind Rags lost S211 phosphorylation and stayed in the nucleus. Endogenous TFEB accumulated in the nucleus after Torin1 or amino-acid starvation and moved back to the cytosol and lysosomes when amino acids were added again. Some MITF isoforms behaved the same way. Boundary: Human cell lines, mostly with overexpressed or mutant proteins; not tested in tissues or whole animals. |
| 2012 | M | MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB MAR2012 Showed mTORC1-dependent TFEB Ser211 phosphorylation: mTORC1 (docked at the lysosome via Ragulator) phosphorylates TFEB on Ser211, which traps it in the cytosol via 14-3-3 proteins. Inhibit mTORC1 and TFEB rushes to the nucleus to switch on autophagy - explaining how mTORC1 controls recycling at the level of gene transcription. |
| 2011 | M | TFEB links autophagy to lysosomal biogenesis SET2011 Showed that TFEB drives a coordinated autophagy and lysosomal gene programme during starvation. In this paper TFEB was regulated by ERK2 phosphorylation; its control by mTORC1 at the lysosome was established in later work (SET2012). |
| 2011 | M | Regulation of TFEB and V-ATPases by mTORC1 PEN2011 Using Tsc2-null and wild-type mouse fibroblasts with and without rapamycin, the authors looked for genes whose expression follows mTORC1 activity and found 75 genes, enriched for subunits of the lysosomal proton pump (V-ATPase). mTORC1 also raised V-ATPase expression in mouse liver after Tsc1 deletion and in a prostate tumour model, through a transcriptional mechanism that needed the transcription factor TFEB: knocking down Tfeb cut the number of mTORC1-induced genes from 1146 to 424 probes, and about a quarter of mTORC1-induced genes depended on Tfeb. mTORC1 promoted albumin uptake (endocytosis) in a Tfeb- and V-ATPase-dependent way. In these serum-deprived cells, active mTORC1 (TSC loss) increased nuclear TFEB and rapamycin or Raptor knockdown reduced it, which is the opposite direction to the TFEB inhibition reported by later studies in fed or starved cells. Boundary: Mostly mouse and human cell lines under low serum; liver and prostate data are expression measurements. The direction of mTORC1 control over TFEB localisation here differs from later work and is condition-dependent. |
| 2009 | M | A gene network regulating lysosomal biogenesis and function SAR2009 The authors found that most lysosomal genes show coordinated expression and share a promoter motif (later called the CLEAR element) that is bound and regulated by the transcription factor TFEB. Under conditions of abnormal lysosomal storage, TFEB moved from the cytoplasm to the nucleus and switched on its target genes. Overexpressing TFEB in cultured cells increased the number of lysosomes and the cells' capacity to degrade complex molecules, including glycosaminoglycans and the mutant huntingtin protein. The paper provided evidence that lysosome production is run by a transcriptional programme with TFEB at its centre, which later work tied to mTORC1 control. Boundary: Cultured cells with TFEB overexpression; mTOR was not studied in this paper. Therapeutic potential for storage and neurodegenerative disease is proposed, not tested. Drafted from the abstract only (no PMC full text). |
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