Autophagy
Cellular recycling process suppressed by mTORC1 and activated upon its inhibition; linked to longevity.
The cell eating its own worn-out parts. The cell's built-in recycling system. mTORC1 normally keeps it switched off; when mTORC1 is blocked, it switches on, clearing out damaged proteins and organelles - and it's linked to longer lifespan.
Regulated at initiation (ULK1), at transcription (TFEB) and at fusion; most 'autophagy is required' claims rest on flux measurements that are hard to do in tissue.
TL;DR. Autophagy appears in 51 curated studies in Oliver's mTOR Atlas: 2 in people (2 human studies); 21 in animal models; 24 at the molecular level (cells, biochemistry, structure); 3 reviews; 1 preprint, not peer-reviewed. It has 2 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 |
| ULK1 activates Autophagy mechanism: functional-consequence · this link in full · on the map table | Freed ULK1 kicks off autophagy – the cell's recycling programme, and the leading idea for why blocking this pathway might be beneficial. Holds under: Mammalian cell studies (GAN2009, HOS2009, EGA2010). Autophagosome initiation is shown in cultured cells. Whether autophagy carries the benefits of mTOR inhibition in whole animals is not tested by these sources. LC3-II accumulation, the standard readout for this step, marks autophagosome number, not flux: it rises whether autophagosomes are being made faster or degraded slower (e.g. under lysosomal/fusion block), so it cannot alone distinguish increased autophagy from stalled autophagy. A flux assay (e.g. LC3-II with and without a degradation blocker, or p62 turnover) is needed to tell the two apart. plausible in people, not shown directly · settled in the literature | M | GAN2009, HOS2009, EGA2010, CHA2007, RUS2013 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 2 |
| A | Animal model | 21 |
| M | Molecular — cells, biochemistry, structure | 24 |
| PP | Preprint, not peer-reviewed | 1 |
| R | Review — secondary literature, not a new result | 3 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | H | Reduced dietary protein intake does not alter autophagy in human blood: A randomized crossover study in healthy adults SIN2026 In a rigorous randomized crossover trial, 63 healthy adults completed both a normal-protein (20% energy) and a reduced-protein (10% energy) diet for 4 weeks each. Despite preclinical evidence that dietary protein restriction should activate autophagy via mTORC1 inhibition, directly measured autophagic flux in blood immune cells did not change between the two diets. This is one of the few human studies to test the protein-restriction-to-autophagy link with a dynamic, flux-based (not just steady-state marker) readout, and the negative result suggests that moderate protein reduction alone, without an accompanying caloric deficit, is not sufficient to engage autophagy in humans the way it does in some animal models. |
| 2026 | H | Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older Adults MOR2026 Autophagy flux in humans is remodeled with age in a sex- and cell-type-specific way, uncoupled from autophagy-gene transcription; in adults over 70, higher PBMC autophagy flux associates with reduced physical function, and 12 weeks of mild exercise lowers PBMC flux while improving function. |
| 2026 | A | Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF SONH2026 Urolithin A ameliorates HFpEF cardiac remodeling in mice by activating AMPK and inhibiting mTOR to restore mitophagic flux, while simultaneously remodeling the gut microbiome-ceramide axis to reduce lipotoxic stress. |
| 2026 | A | Testosterone propionate maintains autophagic flux and mitochondrial integrity via regulation of the LC3B/p62/Beclin-1/mTOR axis in induced liver fibrosis. VER2026 Testosterone propionate protects against CCl4-induced liver fibrosis by maintaining mTOR-regulated autophagic flux via the LC3B/p62/Beclin-1 axis, preserving mitochondrial integrity; castration worsens fibrosis by impairing this pathway. |
| 2026 | A | Notoginsenoside R1 Alleviates Acetaminophen-Induced Liver Injury via MAPK/mTOR-Mediated Autophagy. LIS2026 Notoginsenoside R1 alleviates acetaminophen-induced acute liver injury by activating protective autophagy through MAPK/mTOR pathway modulation, reducing hepatocyte death and oxidative damage. |
| 2026 | A | Chronic Kidney Disease Risk Posed by 1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) Benzene (EDPrB): An AOP of mTOR-Mediated Autophagy Dysregulation. MIAO2026 In mice, the environmental pollutant EDPrB accumulates in the kidney and causes CKD via mTOR hyperactivation, leading to autophagy dysregulation, inflammation and fibrosis; rapamycin rescue identified mTOR as the molecular initiating event, with corroborating data in HK-2 human kidney cells. |
| 2026 | A | Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK YAN2026B Hepassocin (HPS/FGL1), a hepatokine, activates AMPK via an ANXA2-ERK-p90RSK-LKB1 cascade, restraining mTOR activity. Aged HPS-knockout mice show reduced LKB1/AMPK activation and elevated mTOR activity, impaired autophagy, exacerbated cellular senescence, and severely compromised liver regeneration after partial hepatectomy. AMPK agonist AICAR or exogenous HPS rescued the aging/regeneration phenotype. |
| 2026 | A | Role of Autophagy in Scleral Remodeling During Form-Deprivation Myopia WEN2026 Excess scleral autophagy links hypoxic stress to extracellular matrix remodelling in experimental myopia. In form-deprived guinea pigs, subconjunctival rapamycin made myopia worse and 3-MA alleviated it, while atropine slowed myopia and suppressed autophagy-related changes. AMPK/mTOR/P70S6K signalling was measured, but the paper does not establish it as the mediating route. |
| 2026 | A | Corilagin attenuates osteoarthritis progression by coordinating NF-κB inhibition with PI3K/AKT/mTOR-associated autophagy restoration. ZHOU2026B Corilagin restores chondrocyte autophagic flux and ECM synthesis by inhibiting PI3K/AKT/mTOR and NF-κB signalling, reducing cartilage erosion and OARSI scores in the mouse DMM osteoarthritis model. |
| 2026 | A | Early-life exposure to polypropylene microplastics and DEHP induces ASD-relevant neurodevelopmental alterations involving mTOR-regulated autophagy impairment YANG2026 PP-MPs and DEHP activate mTOR and impair autophagy, inducing ASD-like neurodevelopmental deficits in mice; rapamycin rescues autophagic flux and social/behavioral phenotypes. |
| 2026 | A | Dioscorea polystachya Turcz. attenuates male reproductive aging through modulation of mTOR-Beclin-1-mediated autophagy in Leydig and Sertoli cells ZHANG2026B Chinese yam protein extract (CYCSE) attenuates male reproductive aging by activating testicular autophagy through the mTOR-Beclin-1 axis in Leydig and Sertoli cells; mTOR activation blocks protective effects. |
| 2016 | A | Cardioprotection and lifespan extension by the natural polyamine spermidine EIS2016 The mammalian follow-up to EIS2009 and the reason the spermidine branch matters for human health claims: oral spermidine extends mouse lifespan, reduces cardiac hypertrophy and preserves diastolic function, and the protection disappears in mice whose cardiomyocytes lack Atg5, which makes autophagy necessary rather than merely correlated. Boundary: the human part is a dietary questionnaire correlated with blood pressure and cardiovascular incidence, so it is observational and does not carry the causal claim the mouse data carry. |
| 2016 | A | Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. LEL2016 In liver and skeletal muscle from rapamycin-treated marmosets (the earlier pilot cohort), rapamycin was associated with higher expression of PSMB5, a core 20S proteasome subunit, in both tissues but not of PSMB8; proteasome activity itself did not change. Mitochondria-targeted chaperones rose in skeletal muscle but not liver, and autophagy rose in skeletal muscle and adipose tissue but not liver. The authors conclude that only some components of the proteostasis network were upregulated, and in a tissue-specific way. Boundary: tissue samples from a small pilot cohort; the changes are expression-level associations and are not shown to cause any health or lifespan effect. |
| 2013 | A | Overexpression of Atg5 in mice activates autophagy and extends lifespan PYO2013 Mice engineered with extra copies of the autophagy gene Atg5 lived 17% longer and were leaner and more insulin-sensitive. |
| 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. |
| 2012 | A | Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival EFE2012 Rag-GTPase control of mTORC1 is essential for neonatal autophagy and survival to fasting. |
| 2010 | A | Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster BJE2010 Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet. |
| 2010 | A | Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease SPI2010 Connected the longevity drug to a specific age-related disease. Long-term rapamycin prevented memory deficits and lowered toxic amyloid-beta in an Alzheimer's mouse model - and the benefit tracked with INCREASED autophagy in neurons. Suggested that the same autophagy boost that may slow aging could also help clear disease-causing proteins. |
| 2010 | A | Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. CAC2010 Revealed a vicious cycle: amyloid-beta RAISES mTOR activity, and high mTOR in turn blocks the autophagy needed to clear amyloid and tau - so the disease feeds itself. Rapamycin broke the loop in 3xTg-AD mice, rescuing memory and lowering BOTH amyloid and tau, with autophagy induction shown to be necessary for the reduction in amyloid levels. |
| 2009 | A | Induction of autophagy by spermidine promotes longevity EIS2009 The opening paper of the caloric-restriction-mimetic branch: a natural polyamine whose level falls with human age extends lifespan in yeast, flies, worms and human immune cells, and the effect depends on autophagy. In ageing yeast this works through inhibition of histone acetyltransferases, which raises autophagy gene expression. The paper did not measure mTOR, so whether this route bypasses mTOR is not tested here. Boundary: no mammalian lifespan data in this paper. |
| 2008 | A | A role for autophagy in the extension of lifespan by dietary restriction in C. elegans HAN2008 Makes autophagy a necessary step between dietary restriction and a longer life, not a side effect of it: blocking autophagy genes abolishes the lifespan extension produced both by dietary restriction and by TOR inhibition. The paper is equally careful about what autophagy cannot do on its own, because autophagy still runs in animals lacking DAF-16/FOXO and yet those animals are not long-lived. Boundary: worms; necessity was shown, sufficiency was not. |
| 2004 | A | Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease RAV2004 Induced autophagy cleared toxic clumped proteins and improved symptoms in fly (rapamycin) and mouse (the rapalog CCI-779) models of Huntington's disease. |
| 2003 | A | Autophagy genes are essential for dauer development and life-span extension in C. elegans MEL2003 Worms lacking the autophagy gene bec-1 lost the lifespan-extending benefit of reduced insulin-like signaling - autophagy is mechanistically required for daf-2 (insulin-signalling) lifespan extension and for dauer formation in C. elegans. |
| 2026 | M | Molecular and metabolic dysregulation of lung cancer in developing anti-tumor activity by gambogic acid mediated mTOR signaling: in vitro and computational study. BO2026 Computational (network pharmacology and docking) plus in vitro study: gambogic acid is cytotoxic and pro-apoptotic in A549 lung cancer cells and docks most strongly to AKT and the mTOR effector S6K1 (RPS6KB1). Direct mTOR kinase inhibition was not measured; no in vivo or human data. |
| 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 | R | Strengthening Muscle for Healthy Ageing: Innovative Treatments for Sarcopenia ANC2026 A major pharma-facing review (Blau lab, Stanford/Sanford Burnham) surveying emerging drug strategies for sarcopenia — the age-related loss of muscle mass/strength with no approved therapy. Among the pleiotropic mechanisms discussed, mTORC1 inhibitors are highlighted specifically for their ability to restore impaired autophagy in aging muscle, alongside NAD-related molecules, urolithin A, myostatin inhibitors, SARMs, and 15-PGDH ('gerozyme') inhibitors. Useful high-level context for where mTORC1 modulation sits among competing anti-sarcopenia strategies, though it does not itself address dynamic/temporal mTOR activity. |
| 2026 | M | Phosphorylation of OTUB1 promotes autophagy initiation under starvation SUN2026B Under starvation, ERK phosphorylates the deubiquitinase OTUB1 at S118, which stabilizes it by letting it out-compete TRIM29 for binding to ANXA2. Stabilized OTUB1 upregulates DEPTOR, a natural mTOR inhibitor, which suppresses mTOR and triggers autophagy. In mice, restoring this fasting-triggered ERK-OTUB1-DEPTOR-mTOR axis countered the mTOR-activating effect of a Western diet and eased MASLD (fatty liver disease) progression, giving a mechanistic account of how fasting benefits the liver. |
| 2026 | M | An SLC7A5-dependent nutrient-sensing circuit overcomes cisplatin tolerance via mTOR-autophagy signaling. RAO2026 A genome-wide CRISPR screen found that mTOR inhibition promotes cisplatin tolerance by activating cytoprotective autophagy — the opposite of the canonical view. SLC7A5 integrates this mTOR-autophagy axis, and leucine supplementation resensitises SLC7A5-expressing tumour cells to cisplatin. |
| 2026 | M | Brucella suis vaccine strain 2 promotes intracellular proliferation by inducing M2 macrophage polarization and autophagy through PI3K/Akt/mTOR signalling. LI2026B Brucella suis vaccine strain 2 drives mixed M1/M2 macrophage polarisation and autophagic activation in BV2 cells; the M2 state and autophagy synergistically promote intracellular bacterial replication through PI3K/Akt/mTOR signalling. |
| 2026 | M | Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation NAZ2026 Collagen I drives alpha2beta1 integrin-dependent mTORC1/S6 activation and membrane localization of the LAT1-4F2hc amino acid transporter, sustaining essential amino acid supply and cancer cell survival in nutrient-poor, collagen-rich tumor stroma; LAT1-4F2hc is upregulated in basal-like breast/pancreatic tumors and correlates with poor prognosis. |
| 2026 | M | 5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling HAL2026 FOLFOX and oxaliplatin disrupted mTORC1/AMPK regulation of autophagy flux and protein synthesis in cultured myotubes; the effect was not easily reversible on drug withdrawal. Rapamycin (but not metformin) restored autophagy flux and AMPK phosphorylation, though without restoring protein synthesis. |
| 2026 | R | Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration ABR2026 Comprehensive review of how post-translational modifications (phosphorylation, ubiquitination, acetylation, S-acylation, S-nitrosylation) tune SQSTM1/p62's role as the autophagy cargo-receptor hub -- relevant to neurodegenerative disease (Alzheimer's, ALS, Huntington's) where SQSTM1 regulation goes awry. |
| 2024 | M | mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction JOS2024 mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome. |
| 2020 | R | mTOR at the nexus of nutrition, growth, ageing and disease LIU2020 The flagship modern review of the whole field, from Sabatini's own lab (Nature Reviews Molecular Cell Biology). Maps 25+ years of mTOR biology - how it senses nutrients, controls growth and autophagy, and goes wrong in cancer, neurodegeneration, metabolic disease and aging. The single best orientation document for the entire Atlas. |
| 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 | Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism WAN2017 The authors asked whether the transcription factor Nrf2 is needed for rapamycin to hold back cellular senescence. In wild-type mouse fibroblasts exposed to hydrogen peroxide, rapamycin raised Nrf2, switched on autophagy and lowered the senescence markers p16 and p21, beta-galactosidase staining and the inflammatory secretory profile (SASP). In Nrf2-knockout cells rapamycin still lowered beta-galactosidase staining and the SASP, but no longer lowered p16 and p21 or activated autophagy; re-expressing Nrf2 restored those effects, and human WI38 cells with Nrf2 knocked out by CRISPR behaved the same way. In Nrf2-knockout mice given rapamycin (4 mg/kg every other day for 6 weeks, 8 mice per group), fat-tissue beta-galactosidase staining and pro-inflammatory cytokines fell while p16 did not, and rapamycin lowered STAT3 phosphorylation in lung tissue and WI38 cells. The study provided evidence that rapamycin's effect on the SASP can be separated from its Nrf2-dependent effect on cell-cycle arrest. Boundary: Mouse and human fibroblasts in culture plus a short 6-week dosing study in young Nrf2-knockout mice; mTOR inhibition was by rapamycin, which was given before and during the senescence trigger, so this is prevention of senescence onset rather than treatment of established senescent cells. |
| 2016 | M | A systems study reveals concurrent activation of AMPK and mTOR by amino acids DAL2016 Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time. |
| 2013 | M | ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase RUS2013 The authors asked how the ULK1 kinase switches on autophagy when amino acids are withdrawn. In mouse fibroblasts, amino-acid starvation raised the lipid-kinase activity of VPS34 complexes that contain ATG14L while lowering other VPS34 complexes, and the activation needed ULK kinase activity (lost in ULK-deficient and FIP200-null cells). ULK1 directly phosphorylated Beclin-1 at serine 14 (serine 15 in human), shown with purified kinase, mass spectrometry and a phospho-specific antibody; the mTOR inhibitor Torin1 or amino-acid withdrawal raised this phosphorylation only in cells with ULK activity. Cells reconstituted with non-phosphorylatable Beclin-1 S14A did not increase autophagosomes on amino-acid starvation, and the matching worm mutant (BEC-1 S6A) failed to fully rescue autophagic clearance in C. elegans embryos. The work provided evidence for a signalling chain from mTORC1 inhibition to ULK1, Beclin-1 and the ATG14L-VPS34 complex. Boundary: Mouse and human cell lines, in vitro kinase assays and C. elegans embryos; the mTOR step relies on Torin1 (which blocks mTORC1 and mTORC2) and amino-acid withdrawal. Not tested in mammalian tissues or in people. |
| 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 | Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop LOF2011 ULK1 phosphorylates and inhibits AMPK in return, showing autophagy signaling is a bidirectional feedback loop, not a one-way switch. |
| 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 | AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 KIM2011 Revealed the tug-of-war over ULK1: the energy sensor AMPK phosphorylates ULK1 at activating sites to turn autophagy ON when energy is low, while mTORC1 phosphorylates a different site (Ser757) to keep it OFF and even blocks AMPK from reaching ULK1. Two opposing kinases wired to the same switch. |
| 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 | Termination of autophagy and reformation of lysosomes regulated by mTOR YUX2010 Reactivation of mTOR terminates autophagy and drives autophagic lysosome reformation (ALR). |
| 2009 | M | Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy HOS2009 Showed the DIRECT brake mTORC1 uses on autophagy: when nutrients are plentiful, mTORC1 physically joins the ULK1-Atg13-FIP200 complex (the autophagy-starter kinase) and phosphorylates ULK1 to keep it off. Starvation or rapamycin releases this brake and autophagy begins. |
| 2008 | M | Regulation of TORC1 by Rag GTPases in nutrient response KIM2008 Rag GTPases mediate amino-acid signalling to TORC1 (parallel discovery to Sancak 2008). |
| 2007 | M | siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy CHA2007 The authors screened a kinase-targeted siRNA library in human HEK293 cells, using lipidation of the autophagy marker GFP-LC3 after amino-acid starvation as the readout. ULK1 came out of the screen: knocking it down blocked starvation-induced autophagy, while knocking down the related kinase ULK2 did not. ULK1 knockdown also blocked autophagy induced by rapamycin, which fits ULK1 acting downstream of mTOR. Overexpressed ULK1 inhibited autophagy independently of its kinase activity, and the dominant-negative effect mapped to residues 1-351, while the conserved C-terminal domain was needed for ULK1 to reach cytoplasmic structures, some of them LC3-positive. One of the early papers to place ULK1 as a required kinase for starvation-induced autophagy in mammalian cells. Boundary: Cultured human cell lines with siRNA and overexpression; no whole-animal data. The link to mTOR rests on rapamycin-induced autophagy, not on a measurement of mTORC1 acting on ULK1. Drafted from the abstract only (no PMC full text). |
| 2006 | M | Rapamycin alleviates toxicity of different aggregate-prone proteins BER2006 Building on their earlier work with mutant huntingtin, the authors showed in cell models that rapamycin, used as an autophagy inducer, increased the clearance of several proteins with long polyglutamine tracts and of a polyalanine-expanded protein, and reduced their toxicity. In fruit flies expressing wild-type or mutant human tau, rapamycin reduced tau toxicity, and this went with less insoluble tau. The authors argued that inducing autophagy with rapamycin could be useful across several aggregate-prone protein diseases, not only Huntington's disease. Boundary: cultured cells and Drosophila overexpressing disease proteins; drawn from the abstract only; no mammalian in vivo or human data. |
| 2000 | M | Tor-mediated induction of autophagy via an Apg1 protein kinase complex KAM2000 The founding experiment of the whole TOR-to-autophagy axis. Starvation or rapamycin raises the kinase activity of Apg1 (the yeast counterpart of ULK1), and TOR keeps autophagy off by holding Apg13 hyperphosphorylated so that it cannot bind and activate Apg1. Boundary: yeast only, and the mammalian version of the same step (ULK1-ATG13-FIP200) was shown separately nine years later. |
| 2026 | PP | Redox activation of ATG5 licenses autophagy upon nutrient restriction SHI2026 Dietary restriction selectively oxidizes a specific, tissue-resolved set of cysteines rather than oxidizing the proteome broadly. One of the most strongly oxidized is Cys19 on the core autophagy protein ATG5; this oxidation is required for ATG5 to bind ATG10 and form the ATG5-ATG12 conjugate that lipidates LC3B and builds the autophagosome. In mice lacking this redox switch, nutrient restriction fails to trigger autophagy, causing severe tissue pathology and early death -- a single oxidized cysteine gates the autophagic response to fasting. |
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