Pathway link MTORC1-TFEB
mTORC1 TFEB
mTORC1 inhibits TFEB.
Active mTORC1 tags TFEB and traps it outside the nucleus; switch mTORC1 off and TFEB moves in.
The conditions it 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.
- Time it takes
- minutes
- Step
- direct (one molecule acts on the other)
- Measured in
- mammalian cells
- Where in the cell
- lysosome
- Reaches people?
- plausible in people, not shown directly
- How settled
- settled in the literature
Studies behind it
| Year | Evidence | Study |
|---|---|---|
| 2012 | M | The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasisROC2012 mTORC1 phosphorylates TFEB to control lysosomal and autophagy gene transcription. |
| 2012 | M | A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEBSET2012 A lysosome-to-nucleus mechanism uses mTOR-dependent TFEB phosphorylation to sense lysosomal state. |
| 2012 | M | MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEBMAR2012 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 biogenesisSET2011 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). |
| 2022 | M | A Rag GTPase dimer code defines the regulation of mTORC1 by amino acidsGOL2022 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). |
| 2023 | M | Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplexCUI2023 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. |
| 2013 | M | Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomesMAR2013 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. |
Points the other way
| Year | Evidence | Study |
|---|---|---|
| 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. |
| 2011 | M | Regulation of TFEB and V-ATPases by mTORC1PEN2011 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. |
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- Curated by
- Oliver Barton, with AI help for drafting; see how links are checked.
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