Lysosome
The organelle on whose surface mTORC1 is activated. Nutrient signals converge here: mTORC1 must be physically recruited to the lysosomal membrane before Rheb can switch it on.
The place where the decision is made. A cell's recycling center and 'sensing station.' mTORC1 doesn't just float around the cell - it has to physically dock on the lysosome's surface before it can be switched on, so this is where a lot of the pathway's decision-making happens.
Amino-acid sensing, Rheb access, TFEB regulation and autophagosome fusion all happen on or in this one organelle.
TL;DR. Lysosome appears in 24 curated studies in Oliver's mTOR Atlas: 21 at the molecular level (cells, biochemistry, structure); 3 reviews. No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Lysosome required-for mTORC1 mechanism: localisation · this link in full · on the map table | In the amino-acid route, mTORC1 has to travel to the lysosome before it can work, because its activator Rheb waits there. Getting it there and switching it on are two different steps: when researchers glued mTORC1 to the lysosome so it no longer had to be delivered, amino acids stopped making any difference, but the activator was still needed. Holds under: Scoped to amino-acid-driven activation. Live BRET imaging in this corpus (BOU2020) resolves mTOR activity in the cytosol, at the lysosome, in the nucleus and near mitochondria, so mTOR signalling is measurably not one pool. This map draws the lysosomal route and keeps the other localisations declared as open rather than asserting there are none. FER2024 refines this further: lysosomal mTORC1 (fed by local lysosomal proteolysis) and cytoplasmic mTORC1 (fed by exogenous amino acids) phosphorylate distinct downstream substrates — the lysosome is required for one regulatory sub-pool of mTORC1, not for all of it. plausible in people, not shown directly · settled in the literature | M | SAN2010, ZON2011, FER2024, KOR2011, CUI2025 |
| Lysosomal biogenesis activates Lysosome mechanism: functional-consequence · this link in full · on the map table | More, fresher lysosomes change the very platform that controls mTORC1 – closing a loop back to where the signal started. Holds under: SET2012 establishes lysosome-to-nucleus signalling via mTOR and TFEB; the quantitative effect of compartment size on mTORC1 output is not resolved. plausible in people, not shown directly · emerging, few independent studies | M | SET2012, SET2011 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 21 |
| R | Review — secondary literature, not a new result | 3 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 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 | Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1) YIN2026 Cryo-EM structures of human PAT1 (SLC36A1) in apo and substrate-bound states reveal a convergent binding mode for diverse zwitterionic amino acids. This is a structural study; PAT1's role in lysosomal amino acid export and mTORC1 activation comes from earlier work. |
| 2024 | M | Spatial and functional separation of mTORC1 signalling in response to different amino acid sources FER2024 mTORC1 regulation and downstream substrate phosphorylation are spatially separated: lysosomal mTORC1 (fed by local lysosomal proteolysis) and cytoplasmic mTORC1 (fed by exogenous amino acids) phosphorylate distinct substrates depending on amino acid source, challenging the single lysosomal-hub model. |
| 2023 | R | The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease GOU2023 Authoritative review of the molecular basis of nutrient sensing and signalling by mTORC1 in disease. |
| 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). |
| 2021 | M | G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling PRE2021 Adds a physical brake upstream of mTORC1. G3BP1 and G3BP2, known until then as core stress-granule proteins, also sit on the cytoplasmic face of the lysosome and are what holds the TSC complex there; without them TSC cannot reach its target and mTORC1 becomes over-responsive to amino acids and insulin. Loss of G3BP1 reproduces TSC-like hyperactivity phenotypes: faster mTORC1-driven motility in breast cancer cells, with low G3BP1 correlating with worse patient outcome, and disturbed neuronal development in zebrafish. Relevant to the Atlas because it is a lysosomal tethering step that the canonical Rheb/TSC diagram does not show. |
| 2018 | M | NUFIP1 is a ribosome receptor for starvation-induced ribophagy WYA2018 The authors purified lysosomes from human cells and measured how their protein content changes when mTORC1 is switched off by nutrient starvation or by the mTOR inhibitor Torin1, defining 828 lysosome-associated proteins. One responder, NUFIP1 (with its partner ZNHIT3), moved from the nucleus to autophagosomes and lysosomes after mTORC1 inhibition, bound ribosomes from Torin1-treated cells, and bound LC3B directly through a motif lost in the W40A mutant. Without NUFIP1 or its LC3B-binding ability, starvation or Torin1 no longer depleted ribosomal proteins and rRNA, while bulk autophagy and ferritin degradation were unaffected. In cells lacking the GATOR1 subunit DEPDC5, where mTORC1 ignores amino-acid loss, starvation no longer depleted ribosomal proteins but Torin1 still did, which points to mTORC1 inhibition as the trigger. NUFIP1 loss reduced survival under starvation (rescued by nucleosides) and blunted mTORC1 reactivation after long arginine deprivation. Boundary: Human and mouse cell lines over hours of starvation; Torin1 inhibits both mTOR complexes. No tissue or whole-animal data. |
| 2017 | M | Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes ABU2017 Turns the lysosome from a place where mTORC1 is switched on into something mTORC1 also controls: inhibiting mTOR strongly reduces the efflux of most essential amino acids out of the lysosome, so the organelle becomes a store rather than a source. Measured directly by rapidly isolating lysosomes and profiling their contents, which is why the claim is about concentrations inside the organelle and not inferred from signalling readouts. Boundary: one human cell line, acute pharmacological inhibition. |
| 2016 | M | Lysosomal recruitment of TSC2 is a universal response to cellular stress DEM2016 Lysosomal recruitment of TSC2 is a universal response to cellular stress that inhibits mTORC1. |
| 2016 | M | Dynamics of mTORC1 activation in response to amino acids MAN2016 Live imaging shows mTORC1 moves to lysosomes within 2 minutes of amino acid addition and peaks by 5 minutes, in step with leucine arriving in lysosomes; phosphorylation of classic mTORC1 targets lags behind, suggesting mTORC1 passes briefly through the lysosome before acting on substrates elsewhere. |
| 2016 | R | Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot GOB2016 Review: intracellular amino-acid transporters mark the site of mTORC1 activation. |
| 2015 | M | Dynamic Visualization of mTORC1 Activity in Living Cells ZHO2015 TORCAR, described by its authors as the first genetically encoded FRET reporter of mTORC1 activity, lets mTORC1 be watched in living cells as it changes. It showed mTORC1 activity not only at the lysosome but also in the cytosol, nucleus and at the plasma membrane; growth factor spread activity widely, while a leucine surrogate kept it at the lysosome and nucleus. A growth-factor-induced calcium transient contributed to mTORC1 activity. The earliest live reader of mTORC1 held in the atlas. |
| 2015 | M | Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy ARI2015 Extends the mTOR-autophagy relationship to a third form of autophagy that the Atlas otherwise does not cover, and reverses two of its usual terms. Here it is mTORC2, not mTORC1, that sits on the lysosomal membrane, and it inhibits chaperone-mediated autophagy through Akt, while the phosphatase PHLPP1 counteracts it; the balance controls assembly and disassembly of the translocation complex that pulls single proteins into the lysosome. Boundary: mechanism in cells and rodent liver; the claim that restoring this axis helps in ageing or disease is proposed, not tested here. |
| 2014 | M | Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2 DEM2014 Amino-acid starvation recruits TSC2 to the lysosome to inhibit Rheb and TORC1. |
| 2013 | R | Where is mTOR and what is it doing there? BETZ2013 Review of where mTOR localizes and its compartmentalized functions. |
| 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 | Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1 BAR2012 Ragulator was reported as a guanine-nucleotide exchange factor for RagA/B on the lysosome; later work places Ragulator's exchange activity on RagC and assigns RagA GTP loading to SLC38A9, so the tethering role is the better-established one. |
| 2012 | M | SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling KIM2012 SH3BP4 negatively regulates amino-acid-Rag-GTPase-mTORC1 signalling. |
| 2011 | M | mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase ZON2011 Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status. |
| 2011 | M | Lysosomal positioning coordinates cellular nutrient responses KOR2011 Where the lysosome sits inside the cell helps decide whether mTORC1 is on. With nutrients available, lysosomes move to the cell periphery, physically close to the plasma-membrane signalling modules, and mTORC1 is active there; starvation changes intracellular pH and pulls lysosomes into a cluster around the nucleus, where mTORC1 output falls and autophagy is released. Lysosomal position also sets the rate of autophagosome-lysosome fusion, so one variable acts at both the initiation and the termination end of autophagic flux. This added a spatial axis to mTORC1 regulation that Rag/Ragulator recruitment alone does not account for. |
| 2011 | M | Spatial coupling of mTOR and autophagy augments secretory phenotypes NAR2011 Protein synthesis and autophagic degradation are usually described as opposites that mTOR switches between, and this paper shows a compartment where the cell deliberately runs both at once. In senescent cells, autolysosomes and mTOR gather at one side of the Golgi (the TASCC), mTOR gets there in an amino-acid- and Rag-dependent way, and destroying that arrangement cuts interleukin-6/8 secretion. Boundary: cells, not organisms; it explains how the senescent secretory programme is fuelled, not whether blocking it helps an animal. |
| 2010 | M | Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids SAN2010 Established WHERE mTORC1 gets switched on: the lysosome surface. Identified Ragulator as the lysosomal dock that recruits the Rag GTPases and drags mTORC1 to the membrane where its activator Rheb lives. Amino acids work by controlling this translocation. |
| 2010 | M | Termination of autophagy and reformation of lysosomes regulated by mTOR YUX2010 Reactivation of mTOR terminates autophagy and drives autophagic lysosome reformation (ALR). |
| 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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