The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex
Open accessAbstract
The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“mTORC1 is regulated by a wide range of nutrients and hormonal cues, most notably the availability of amino acids, but also glucose, oxygen, and cholesterol 1–3.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [1]
Experimental — accuracy not yet measuredIn the citing paper
“and comparisons of circulating testosterone between vegans and omnivores have revealed no differences [132].”
From Nutritional Considerations for the Vegan Athlete (2023) · cites this paper as [132]
In the citing paper
“However, there is currently no evidence suggesting that vegans are deficient in the fat-soluble vitamins, and comparisons of circulating testosterone between vegans and omnivores have revealed no differences [132].”
From Nutritional Considerations for the Vegan Athlete (2023) · cites this paper as [132]
In the citing paper
“Additionally, NPC1 has been implicated in cholesterol-dependent signaling to mTORC1 through SLC38A9 (Castellano et al., 2017)”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Castellano et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Watterson, K. R., Bestow, D., Gallagher, J. R., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2012) · Neurosignals · doi:10.1159/000334144 · Cited by 3,395
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M. (2008) · Science · doi:10.1126/science.1157535 · Cited by 2,773
Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464
Self-citationActivation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020
Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity
Um, S. H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P. R., Kozma, S. C., Auwerx, J., et al. (2004) · Nature · doi:10.1038/nature02866 · Cited by 1,677
Zoncu, R., Bar-Peled, L., Efeyan, A., Wang, S., Sancak, Y., & Sabatini, D. M. (2011) · Science · doi:10.1126/science.1207056 · Cited by 1,673
Self-citation[19] Receptor-mediated endocytosis of low-density lipoprotein in cultured cells
Goldstein, J. L., Basu, S. K., & Brown, M. S. (1983) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(83)98152-1 · Cited by 1,629
Protein Sensors for Membrane Sterols
Goldstein, J. L., DeBose-Boyd, R. A., & Brown, M. S. (2006) · Cell · doi:10.1016/j.cell.2005.12.022 · Cited by 1,517
Regulation of TORC1 by Rag GTPases in nutrient response
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P., & Guan, K.-L. (2008) · Nature Cell Biology · doi:10.1038/ncb1753 · Cited by 1,349
A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins
Goldstein, J. L., & Brown, M. S. (2015) · Cell · doi:10.1016/j.cell.2015.01.036 · Cited by 1,233
Flagged first, then by citations
Cited by
Sorted by citations
Items 401–500 of 561
Lamming, D. W. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823679-6.00002-3 · Cited by 4
Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1
Martins, T. S., Costa, R. S., Vilaça, R., Lemos, C., Teixeira, V., Pereira, C., & Costa, V. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076221 · Cited by 6
Berquez, M., Chen, Z., Festa, B. P., Krohn, P., Keller, S. A., Parolo, S., Korzinkin, M., Gaponova, A. V., Laczkó, E., Domenici, E., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.28.505580 · Cited by 4
Lu, W., Huang, J., Zhang, Z., Jia, S., Zhao, W., Li, L., Niu, F., Fang, K., Cai, Z., Li, Y., et al. (2025) · Advances in Redox Research · doi:10.1016/j.arres.2025.100130 · Cited by 3
Li, J., He, L., Wang, S., Li, W., Wang, X., Li, E., Qin, J., & Chen, L. (2025) · Aquaculture · doi:10.1016/j.aquaculture.2025.743129 · Cited by 3
Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction
Methorst, J., Verwei, N., Hoffmann, C., Chodnicki, P., Sansevrino, R., Pyne, P., wang, H., van Hilten, N., Aschmann, D., Kros, A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63769-5 · Cited by 3
Chen, J., Chen, M., Hu, J., Wu, Z., Li, H., Li, W., He, F., Peng, C., Xu, Y., Huang, W., et al. (2025) · Journal of the American Heart Association · doi:10.1161/jaha.125.045554 · Cited by 3
Non-canonical roles of lysosomes in neurons
Spencer, J. I., Sudarikova, Y., & Devine, M. J. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.10.009 · Cited by 4
Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders
Puszynska, A. M., Nguyen, T. P., Cangelosi, A. L., Armani, A., Roberts, J. M., Singh, K. A., Cameron, J. C., Tseyang, T., Liu, G. Y., Lai, S., et al. (2026) · Science · doi:10.1126/science.ady0832 · Cited by 8
Azaria, R. D., Correia, A. B., Schache, K. J., Zapata, M., Pathmasiri, K. C., Mohanty, V., Nannapaneni, D. T., Ashfeld, B. L., Helquist, P. M., Wiest, O., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.179525 · Cited by 3
“JCI Insight 2024;9(20):e179525 https://doi.org/10.1172/jci.insight.179525 signaling (15, 16), lysosomal membrane permeabilization (16–18), and mitochondrial abnormalities (13, 19).”
BackgroundInfluentialPhosphoinositides as regulators of membrane contact sites
Haukaas, H. S., & Stenmark, H. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2025.159673 · Cited by 3
Does mTORC1 inhibit autophagy at dual stages?
Santhaseela, A. R., & Jayavelu, T. (2020) · Bioessays · doi:10.1002/bies.202000187 · Cited by 3
Wüstner, D., Juhl, A. D., Egebjerg, J. M., Werner, S., McNally, J. G., & Schneider, G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1144936 · Cited by 3
Cholesterol and Cholesterol-Lowering Medications in COVID-19—An Unresolved Matter
Grewal, T., Nguyen, M. K. L., & Buechler, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910489 · Cited by 5
“SLC38A9 forms a complex with NPC1, which in turn activates the mechanistic target of rapamycin complex 1 (mTORC1) in a cholesterol-sensitive manner [61,62].”
BackgroundYang, S., Chen, J., Xie, K., & Liu, F. (2024) · FEBS Open Bio · doi:10.1002/2211-5463.13951 · Cited by 3
“The mechanisms include matrix metalloprotease (MMP) secretion, chaperone-mediated autophagy or mTORC1 signaling [39], focal adhesion assembly [40,41], Src localization and signaling, cholesterol-sensitive SNARE functioning in exocytic pathways [42], caveolae formation [43], and fibronectin secretion…”
Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate
Wang, Z., He, J., Yang, Y., He, Y., & Qian, H. (2025) · Nature Communications · doi:10.1038/s41467-025-58087-9 · Cited by 3
Wüstner, D. (2019) · Theoretical Biology and Medical Modelling · doi:10.1186/s12976-019-0108-2 · Cited by 4
Zhang, Y., Yang, X. W., Yao, J., Ren, Y., & Liu, P. (2022) · Disease Markers · doi:10.1155/2022/3276925 · Cited by 4
Assmann, J. C., Brender, J., Farthing, D. E., Saito, K., Kishimoto, S., Warrick, K. A., Maglakelidze, N., Crooks, D. R., Merkle, H., Gress, R. E., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/809327 · Cited by 3
“Cholesterol binding directly activates mTORC1 (53), the Smoothened receptor (54), and multiple signaling proteins containing PDZ domains with the CRAC motif (55) resulting in the activation of several major pathways associated with cell division, differentiation, invasion, and metastasis including the MAPK/ERK, Hedgeh…”
BackgroundNutrient signaling pathways regulate amyloid clearance and synaptic loss in Alzheimer’s diseasePreprint
Mondal, M., Bali, J., Tzioras, M., Paolicelli, R. C., Jawaid, A., Malnar, M., Dominko, K., Udayar, V., Halima, S. B., Vadodaria, K. C., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.13.381186 · Cited by 3
“Recent studies demonstrate that lysosomal cholesterol can increase protein synthesis via activating mTORC1, a master regulator of cell growth (Castellano et al., 2017).”
BackgroundNg, M. Y. W., Charsou, C., Lapão, A., Singh, S., Trachsel-Moncho, L., Nakken, S., Munson, M. J., & Simonsen, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.04.455032 · Cited by 3
Unraveling the Connection: Cholesterol, Calcium Signaling, and Neurodegeneration
Casas, M., & Dickson, E. J. (2024) · Neuroscience Insights · doi:10.1177/26331055241252772 · Cited by 3
“…more than one molecular mechanism may contribute to neuronal loss in NPC. Supporting complex disease pathogenesis, research has shown that various signaling pathways such as mTORC1, 40 autophagy, 41 mitochondrial dysfunction, 42 and STING signaling 43 are differentially regulated in NPC disease.”
BackgroundKorbonits, M., Wang, X., Barry, S., Lim, C. T., Suleyman, O., Tito, S. D., Uddin, N., Vignola, M. L., Hall, C. L., Perna, L., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.08.604602 · Cited by 3
ATR promotes mTORC1 activity via de novo cholesterol synthesis
Tangudu, N. K., Grumet, A. N., Fang, R., Buj, R., Cole, A. R., Uboveja, A., Amalric, A., Yang, B., Huang, Z., Happe, C., et al. (2025) · EMBO Reports · doi:10.1038/s44319-025-00451-3 · Cited by 5
“…including cholesterol, amino acids, and glucose, promote mTORC1 localization to the lysosome where it can be activated by the small GTPase Rheb (Castellano et al, 2017; Saxton and Sabatini, 2017; Shin et al, 2022). mTORC1 activation also requires inhibition of its upstream negative…”
InfluentialNFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency
Cendrowski, J., Wróbel, M., Mazur, M., Jary, B., Maurya, R., Wang, S., Korostyński, M., Dziewulska, A., Rohm, M., Kuropka, P., et al. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05490-y · Cited by 2
“…lysosome-derived nutrients to the cell is sensed by lysosome-associated signaling pathways [16] , including signaling of mechanistic Target of Rapamycin Complex 1 (mTORC1) that is activated by lysosome-derived amino acids or cholesterol to promote anabolic and inhibit catabolic pathways [17, 18] .”
Lin, X., Ma, C., Zhang, X., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-03781-3 · Cited by 2
“The activation of mTORC1 by cholesterol relies on the presence of conserved cholesterol-responsive motifs in SLC38A9 , a transmembrane protein located in the lysosome 21 .”
Long, C. C., Festa, L. K., Cruz‐Berrios, M., Johnson, T. D., Mitchell, C. H., Jordan‐Sciutto, K. L., & Grinspan, J. B. (2025) · Glia · doi:10.1002/glia.70050 · Cited by 2
“Evidence from HEK293t cells indicates that mTORC1 remains attached to the lysosome under conditions of high lysosomal cholesterol, retaining TFEB in a phosphorylated state, resulting in cytosolic localization and reducing lysosome biogenesis (Castellano et al. 2017).”
Amino acid and cholesterol metabolism in innate immunity
Li, W., Jin, M., Li, H., Zhong, R., Lin, Z., Shen, M., & Wang, H. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.09.019 · Cited by 3
Zhou, S., Li, N., Li, R., Ding, Y., Zhu, Y., Pan, Y., Liu, Y., Zhang, Y., Yang, H., & Wang, Q. (2026) · iScience · doi:10.1016/j.isci.2026.115017 · Cited by 2
“24 In addition, NPC2 binds free cholesterol (FC) and transports it out of lysosomes for further processing.”
Lipid signaling networks in pancreatic cancer progression and therapeutic perspectives
Costamagna, A., Milan, G., Santis, M. C. D., Carrer, A., & Martini, M. (2026) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2026.03.004 · Cited by 2
Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1
Zhong, Y., Sahan, A. Z., Shao, Z., Zhang, Q.-Y., Zhou, X., Haggett, J. G., Koshizuka, K., Myers, S. A., Gutkind, J. S., & Zhang, J. (2026) · Nature Chemical Biology · doi:10.1038/s41589-026-02188-z · Cited by 2
“Although the present study focused on growth-factor-stimulated mTORC1, other stimuli also activate mTORC1 at different subcellular locations 8,13,73 .”
Niemann-Pick Type C Disease: At the Nexus of Neurodegenerative and Neurodevelopmental Disorders
(2020) · Journal of Parkinson’s Disease and Alzheimer’s Disease · doi:10.13188/2376-922x.1000029 · Cited by 2
TorS ‐ Reframing a rational for type 2 diabetes treatment
Bar‐Tana, J. (2023) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3712 · Cited by 2
“…may be hyper ‐ activated by growth factors (e.g., insulin, IGF1), 17,19 energy/nutrients excess (e.g., glucose, 23 amino acids, 24 cholesterol 25 ) and inflammation (e.g., NFkB/IKK), 26 while being suppressed by metabolic stress (e.g., caloric, hypoxic, hyperosmotic, oxidative, acidic, DNA…”
BackgroundBorsato, G., Carnio, F., Lunardon, S., Moletta, M., Pavan, G., Terrin, F., Scarso, A., Plotegher, N., & Fabris, F. M. (2024) · Chemistry - A European Journal · doi:10.1002/chem.202400778 · Cited by 2
Ali, T., Jan, I., Ramachandran, R., et al. (2024) · In Silico Pharmacology · doi:10.1007/s40203-024-00259-4 · Cited by 2
G-quadruplex in cancer energy metabolism: A potential therapeutic target
Han, Z., & Wen, L. (2025) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2025.130810 · Cited by 2
HR3/RORα-mediated cholesterol sensing regulates TOR signaling
Lassen, M., Pardee, K., Bradić, I., Pedersen, L. H., Kubrak, O. I., Ahrentløv, N., Clancy, S., Koyama, T., Necakov, A., Liu, S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71059-x · Cited by 3
“In mammalian cell culture, cholesterol has emerged as a key factor that activates the TOR pathway 3,14 .”
InfluentialHow NPC1 Loss Twists the TORCque of Lysosomes
Henne, W. M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.01.007 · Cited by 2
Cholesterol feeds into cell growth control
Strzyz, P. J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.41 · Cited by 2
Cholesterol metabolism in prostate cancer
Koltai, T., Reshkin, S. J., Baltazar, F., & Fliegel, L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-90528-2.00007-2 · Cited by 2
Guo, H., Zhu, Y., Li, J., Zhang, Q., & Yan, C. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120888 · Cited by 2
Autophagy and hepatic steatosis
Sparks, C. E., & Sparks, J. D. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000436 · Cited by 2
Egg Protein in Sports Nutrition
Martinez, I. G., McKenna, C. F., & Burd, N. A. (2019) · Royal Society of Chemistry eBooks · doi:10.1039/9781788013833-00102 · Cited by 2
Surviving starvation simply without TFEB
Soukas, A. A., & Zhou, B. Z. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000285 · Cited by 3
Insulin Signaling Couples Growth and Early Maturation to Cholesterol IntakePreprint
Texada, M. J., Lassen, M., Pedersen, L. H., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.07.447368 · Cited by 2
“26 We wished to determine whether, and the routes by which, cholesterol might regulate Drosophila larval growth.”
InfluentialThe Lysosome Signaling Platform: Adapting With the Times
Inpanathan, S., & Botelho, R. (2023) · doi:10.32920/21982901 · Cited by 2
IL-4 Licenses B Cell Activation Through Cholesterol SynthesisPreprint
Steach, H. R., York, A. G., Mattingly, J. R., Skadow, M. H., Chen, S., Zhao, J., Williams, K. J., Zhou, Q., Hsieh, W.-Y., Brewer, J. R., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.13.593964 · Cited by 3
“Phosphorylation of S6 kinase by mTORC1 occurs downstream of BCR/CD40, and stability of the mTORC1 complex has been shown to require lysosomal cholesterol in cell lines 23,24 .”
BackgroundAtlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated MetabolitesPreprint
Puszynska, A. M., Nguyen, T. P., Cangelosi, A. L., Armani, A., Roberts, J. M., Singh, K. A., Cameron, J. C., Tseyang, T., Liu, G. Y., Lai, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.25.678303 · Cited by 2
The role of lysosomes in autophagy
Rabanal‐Ruiz, Y., & Korolchuk, V. I. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822003-0.00007-3 · Cited by 1
Membrane contact sites orchestrate cholesterol homeostasis that is central to vascular aging
Li, W., Pang, Y., Jin, K., Wang, Y., Wu, Y., Luo, J., Xu, W., Zhang, X., Xu, R., Wang, T., et al. (2023) · WIREs Mechanisms of Disease · doi:10.1002/wsbm.1612 · Cited by 1
Bone, B., Griffith, L., Jefferson, M. A., Yamauchi, Y., Wileman, T. E., & Powell, P. P. (2025) · Autophagy · doi:10.1080/15548627.2025.2482516 · Cited by 1
“OSBP mediates cholesterol transfer from the endoplasmic reticulum to lysosomes at membrane contact sites [42] and reverse transfer to the ER is facilitated by OSBPL1A/ORP1 and OSBPL5/ ORP5 [43].”
Cholesterol finds its pocket in LYCHOS
Shin, H. R., & Zoncu, R. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01551-3 · Cited by 1
Intracellular cholesterol: new functions and therapeutic approaches in NSCLC EGFR-TKI resistance
Wang, L., Qiu, Y., Huang, X., Zhang, S., Zhao, M., & Chen, Q. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02559-w · Cited by 1
Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation
Milan, G., Mareninova, O. A., Fantuz, M., Spacci, M., Paoli, C., Pineda, J. A., Noè, R., Calciolari, B., Zoncu, R., Gukovskaya, A. S., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102292 · Cited by 1
“Decreased levels of NPC1 cause alterations in cholesterol trafficking and its accumulation within lysosomes [34], where is sensed by the Ragulator complex and promotes mTORC1 activation [14,15].”
Pirone, D., di Summa, M., Mosca, N., Giugliano, G., Schiavo, M., Agostino, M. D., Medina, D. L., Bianco, V., Miccio, L., Memmolo, P., et al. (2025) · Journal of Physics Photonics · doi:10.1088/2515-7647/ae2f86 · Cited by 1
“Moreover, NPC1 dysfunction also affects nucleolar function via altered lipid homeostasis and activation of stress pathways such as mTORC1 [58, 59].”
NMNAT1 Activates Autophagy to Delay D‐Galactose‐Induced Aging in Cochlear Hair Cells
Wei, Y., Yang, W., Wu, H., Kong, M. L., Fan, D., Zhang, Y., Cheng, N., Du, J., Guo, L., Li, Y., et al. (2026) · Aging Cell · doi:10.1111/acel.70373 · Cited by 1
“Dysregulation of glucose and cholesterol affects the mTOR and AMP-activated protein kinase signaling pathways, impairing autophagy, and promoting aging (Castellano et al. 2017; Wolfson et al. 2017; Zhou et al. 2017).”
Ni, Z., Wang, R., Miao, H., Wang, G., Lim, W. L. F., Zhang, S., Lam, S. M., & Shui, G. (2026) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2026.02.067 · Cited by 1
Molecular and structural mechanisms of nutrient sensing in the mTORC1 pathway
Yang, S., Bian, T., & Zoncu, R. (2026) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2026.02.009 · Cited by 3
Fatty acid synthesis supports tumor progression through facilitating the activity of TORC1 signaling
Károlyi, D., Botor, B. S., Neuhauser, N., Rubics, A., Szinyákovics, J., Kovács, T., Péter, M., Balogh, G. E., O’Farrell, F., & Takáts, S. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08738-6 · Cited by 1
“In addition to Insulin/PI3K and nutrient availability [11, 12, 25], AMPK-mediated inhibitory phosphorylation is another critical regulator of TORC1.”
Wang, D., Zhang, J., Zhuang, Z., et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104210 · Cited by 1
“Given the established crosstalk between mTORC1 activity and arginine availability [49], and supported by our metabolomic data showing VK-induced accumulation of arginine-pathway intermediates, these findings indicate that VK coordinates arginine metabolism through the AMPK/mTOR signalling axis.”
Kawachi, Y., Koçak, G., Korolchuk, V. I., Kataura, T., & Sarkar, S. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1857866 · Cited by 2
Global cellular responses to lysosomal damage
Jia, J. (2026) · Current Biology · doi:10.1016/j.cub.2026.05.050 · Cited by 2
Buendia-Nacarino, M. P., Bulfon, D., Tom, N., Rohde, M., Bilgin, M., Jäättelä, M., Mena, M. L., García, R. Á.-F., & Luque-Garcia, J. L. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18080919 · Cited by 1
“Importantly, the combination of altered cholesterol metabolism and lysosomal damage (as demonstrated by Gal3 puncta formation) suggests dysfunction of the lysosome–mTORC1 axis [52].”
The tuberous sclerosis complex gets fatter
Gokare, P. R., & El‐Deiry, W. S. (2017) · Oncotarget · doi:10.18632/oncotarget.18436 · Cited by 1
Suppressing mTORC1 on the lysosome
Raiborg, C., Schink, K. O., & Stenmark, H. (2017) · The EMBO Journal · doi:10.15252/embj.201797469 · Cited by 1
“A recent study has also revealed the involvement of another lipid in mTORC1 signalling, namely lysosomal cholesterol, which controls the membrane recruitment and activation of mTORC1 by a mechanism similar to that of amino acids (Castellano et al , 2017).”
Enhanced activation of mechanistic target of rapamycin complex 1 signaling in eruptive xanthomas
Huang, Y., Cui, B., Bai, Y., et al. (2023) · JAAD International · doi:10.1016/j.jdin.2023.07.001 · Cited by 1
New tools can propel research in lysosomal storage diseases
Hertz, E., Glasstetter, L. M., Chen, Y., & Sidransky, E. (2023) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2023.107729 · Cited by 1
Assessment of genes involved in lysosomal diseases using the ClinGen Clinical Validity framework
Groopman, E., Mohan, S., Waddell, A., Wilke, M. V. M. B., Fernandez, R., Weaver, M. A., Chen, H., Liu, H., Bali, D. S., Baudet, H., et al. (2024) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2024.108593 · Cited by 1
Jefcoate, C. R. E., Larsen, M. C., Song, Y., Maguire, M., & Sheibani, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052011 · Cited by 2
“The cholesterol-Slc38a9 complex recruits a multiprotein complex; the mTORC1 complex [88,89].”
Gut-derived hormones in insects
Rewitz, K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-323-95424-2.00014-5 · Cited by 2
Xiong, X., Lv, D., Liu, Y., et al. (2019) · British Journal Of Nutrition · doi:10.1017/s0007114519002629 · Cited by 1
Zooming in on the cell biology of disease
Perera, R. M. (2021) · Molecular Biology of the Cell · doi:10.1091/mbc.e21-09-0459 · Cited by 1
“Through collaboration with colleagues, we have helped to uncover how autophagy and lysosomes contribute to cellular differentiation, exosome biogenesis, and nutrient sensing (AltshulerKeylin et al., 2016; Castellano et al., 2017; Kilinc et al., 2021).”
BackgroundBirolini, G., Valenza, M., Paolo, E. D., Vezzoli, E., Talpo, F., Maniezzi, C., Caccia, C., Leoni, V., Bocchi, V. D., Conforti, P., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.13.092742 · Cited by 1
“Moreover, an increase in lysosomal cholesterol has been reported to activate mTORC1 (65), and cholesterol is reduced in HD lysosomes (66).”
BackgroundSchmeisser, K., Kaptan, D., Raghuraman, B. K., Shevchenko, A., Penkov, S., & Kurzchalia, T. (2022) · bioRxiv · doi:10.1101/2022.08.26.505407 · Cited by 2
“in vitro [16], during dauer exit to push protein synthesis and growth.”
BackgroundInfluentialMalonyl-CoA is an ancient physiological ATP-competitive mTORC1 inhibitorPreprint
Nicastro, R., Brohée, L., Alba, J., Nüchel, J., Figlia, G., Kipschull, S., Gollwitzer, P., Romero‐Pozuelo, J., Fernandes, S., Lamprakis, A. A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.06.515351 · Cited by 1
Role of lysosome-associated membrane protein, Lamp1, in Drosophila melanogaster
Chaudhry, N. Y. (2023) · doi:10.31274/td-20240617-261 · Cited by 1
Senescent cell survival relies on upregulation of lysosomal quality control mechanismsPreprint
Curnock, R., & Carroll, B. (2025) · bioRxiv · doi:10.1101/2025.03.31.646397 · Cited by 1
“…elegantly demonstrated the role of the lysosome in detecting cholesterol and identified cholesterol sensing machinery that promote the recruitment of mTORC1 to lysosomes (Bayly-Jones et al., 2024; Castellano et al., 2017; Lim et al., 2019; Shin et al., 2022; Xiong et al., 2025; Zhao et al., 2025).”
Papers of note in Science 355 (6331)
VanHook, A. M. (2017) · Science Signaling · doi:10.1126/scisignal.aan2959
Yambire, K. F. (2018) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7142
Andrade, M. L. (2019) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2019.tde-18092019-161605
Organelle dysfunction modulates cholesterol biosynthesis pathway
Pereyra, L. (2019) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7666
Dzichenka, Y. U., Horetski, M. S., Faletrov, Y. V., Yantsevich, А. V., Shkumatov, V. M., & Usanov, S. A. (2020) · Doklady of the National Academy of Sciences of Belarus · doi:10.29235/1561-8323-2020-64-5-558-566
The Mammalian Target of Rapamycin Complex 1 (mTORC1): An Ally of M. tuberculosis in Host Cells
Bruiners, N., Guerrini, V., & Gennaro, M. L. (2020) · Springer eBooks · doi:10.1007/978-3-030-56905-1_3
Golden, C. K. (2021) · Spectrum Research Repository (Concordia University)
Slade, L., & Pulinilkunnil, T. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822003-0.00005-x
Anand, P. (2021) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736651236.793581802
Lipid antigens in adipose tissue
van Eijkeren, R. J. (2022) · doi:10.33540/1201
Mitogenic and Metabolic signals regulate mTOR complex 1 function to control GSK3β nuclear program
Bautista, S. J. (2021) · doi:10.32920/ryerson.14654061.v1 · Cited by 1
Rehling, P., & Callegari, S. (2017) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727874366.793538463
Faculty Opinions recommendation of Signaling networks in immunometabolism.
Kane, L. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737610223.793578145
Genome-wide analysis of dendritic cell differentiationPreprint
Tiniakou, I., Hsu, P.-F., López-Zepeda, L. S., Lau, C. M., Soni, C., Esteva, E., Adams, N. M., Liu, F., Khodadadi‐Jamayran, A., Rodrick, T. C., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.11.491577
Stress granules and Sec bodies: From Drosophila to mammalian cells.
van Leeuwen, W. (2022) · Utrecht University Repository (Utrecht University) · doi:10.33540/1234
mTORC1: Upstream and Downstream
Yao, Y., & Inoki, K. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821618-7.00182-6
Disrupted cellular quality control mechanisms in aging
Carvalho, C., Pires, J. F., Moreira, P. I., & Raimundo, N. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-823761-8.00016-1
Wicks, I. P., Kim, M. L., Souza, D. P. D., Narayana, V. K., Nguyen, N. C., & Sleebs, B. E. (2022) · Research Square · doi:10.21203/rs.3.rs-2299218/v1
The Lysosome Signaling Platform: Adapting With the Times
Inpanathan, S., & Botelho, R. (2023) · doi:10.32920/21982901.v1
Adaptations of autophagy and lysosomal systems upon membrane damage and pathogenic invasion
Bhattacharya, A. (2023) · Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) · doi:10.21248/gups.73735
Bone, B., Griffith, L., Jefferson, M. A., Yamauchi, Y., Wileman, T. E., & Powell, P. P. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.09.627529
Xu, A. E., & Weissman, J. S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.23.630120
Illuminating cholesterol-mTORC1 signaling: LYCHOS in focus
Shin, H. R., & Zoncu, R. (2025) · Structure · doi:10.1016/j.str.2025.01.009
Metadata
- Authors
- Castellano, B. M., Thelen, A. M., Moldavski, O., Feltes, M., van der Welle, R. E. N., Mydock-McGrane, L., Jiang, X., van Eijkeren, R. J., Davis, O. B., Louie, S. M., Perera, R. M., Covey, D. F., Nomura, D. K., Ory, D. S., & Zoncu, R.
- Affiliations
- University of California, Berkeley (US)
- Washington University in St. Louis (US)
- Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
- University of California, San Francisco (US)
- Corresponding author
- Castellano, Brian M.
- Thelen, Ashley M.
- Zoncu, Roberto
- ORCID
- Venue
- Science
- Published
- 2017-03-24
- Volume
- 355
- Issue
- 6331
- Pages
- 1306-1311
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5823611
- OpenAlex
- W2603916465
- Semantic Scholar
- 0cc6e6385fc09089703fcae595ecd7b42ea20c97
- Cited by
- 562
- References
- 36
- Citations by year
- 2026: 40 · 2025: 65 · 2024: 57 · 2023: 77 · 2022: 70 · 2021: 63 · 2020: 69 · 2019: 58 · 2018: 41 · 2017: 22
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (1DP2CA195761-01)
- Pew-Stewart Scholarship for Cancer Research
- Damon Runyon-Rachleff Innovation Award
- Edward Mallinckrodt, Jr. Foundation
- National Institutes of Health (R01 HL067773)
- Taylor Family Institute for Innovative Psychiatric Research
- National Science Foundation (DGE 1106400)
- Howard Hughes Medical Institute Gilliam Fellow
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- mTORC1, lysosomal cholesterol, SLC38A9, Niemann-Pick C1, lysosomes, sterol transport, nutrient signaling, growth regulation, arginine sensing, protein complexes
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Biological Transport, Carrier Proteins, Cholesterol, Cricetulus, Enzyme Activation, Fibroblasts, Humans, Cholesterol, HDL, Lysosomes, Mutation, Nuclear Proteins, Signal Transduction, CHO Cells, Amino Acid Motifs, Amino Acid Transport Systems, Multiprotein Complexes, Mice, HEK293 Cells, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
