Cell Biology of Nutrient Sensing

Because nutrients are the building blocks for cells to grow and proliferate, nutrient sensing mechanisms ensure that cells only grow when all necessary elements are available and all conditions are optimal. Our work investigates the intricate molecular and cellular mechanisms that govern cell growth, metabolism, and protein recycling in nutrient sufficiency, starvation or stress; and reciprocally connect these processes to secretory pathway activity and the ECM.

Due to its role as a primary hub in metabolic and nutrient signaling, and a key regulator of virtually all cellular functions, most of our projects center around the master cellular nutrient sensor and growth coordinator, the mTOR kinase; and its main negative upstream regulator, the tumor suppressor TSC complex (Tuberous Sclerosis Complex). Furthermore, given the central function of mTOR in the ageing process—and that dysregulation of the nutrient sensing machinery is a hallmark of ageing—our research investigates fundamental aspects of healthy ageing and age-related diseases.

To achieve this, we combine high-throughput omics approaches (functional genomic screens, proteomics, metabolomics, interactome/proximome analyses) with state-of-the-art molecular biology, biochemistry, cell biology, gene-editing, and high-resolution microscopy techniques. We make use of established human and mouse cell lines, cancer cell lines, patient-derived cells, as well as model organisms (together with our collaborators), to identify evolutionarily conserved processes and to address multiple fundamental questions. Overall, our vision is to understand: i) how mammalian cells sense the availability of nutrients and the presence of stresses in their environment to adjust their metabolism, growth, and other functions accordingly, ii) how the dysregulation of these cellular mechanisms contributes to the development of human diseases and to the ageing process, and iii) how we can intervene—pharmacologically or nutritionally—to efficiently and specifically target such life-threatening conditions.

• Nüchel J.#, Omidi M., Fernandes SA., Tauber M., Pohl S., Plomann M., and Demetriades C.#, GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi. EMBO Reports. 2026 Apr 16. doi:10.1038/s44319-026-00773-w
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• Pan J., Teleman A.A., and Demetriades C.#, ATM-dependent RHEB phosphorylation couples DNA damage to lysosomal mTORC1 signaling to orchestrate the cellular response to genotoxic stress. bioRxiv. 2026 Jan 17; doi:10.64898/2026.01.16.699946.
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• Fernandes S.A.#, Pan J., Terziyska D.S., Koyuncu S., Ding X., Németh I.B., Wilhelm S., Nüchel J., Al-Gburi S., Gonidas C., Pasparakis M., Mosialos G., Széll M., Teleman A.A., Eming S.A., Vilchez D., and Demetriades C.#, The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity. bioRxiv. 2025 Sep 2; doi:10.1101/2025.09.01.673523.
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• Kawamura K.*, Diederich AR.*, Gerisch B., Ripa R., Latza C., Steiner J.D., Fernandes SA., Artoni F., Meyer DH., Sant D., Oehm S., Grundmann F., Müller R.-U., Demetriades C.#, and Antebi A.#, Resilience and restoration from fasting-refeeding mediated by a nutrient-regulated linker histone. bioRxiv. 2025 Apr 19; doi:10.1101/2025.04.14.648802.
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• Bubb K., Etich J., Probst K., Parashar T., Schuetter M., Dethloff F., Reincke S., Nolte JL., Krüger M., Schlötzer-Schrehard U., Nüchel J., Demetriades C., Giavalisco P., Riemer J., and Brachvogel B., Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging. Science Advances. 2025 April 18;11(16):eads1842. doi: 10.1126/sciadv.ads1842
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• Lamprakis A., and Demetriades C.#, TSC1 phosphorylation by lysosomal mTORC1 establishes a minimal autoregulatory feedback loop. bioRxiv. 2025 Jan 15; doi:10.64898/2026.01.15.699678.
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• Perri G., French C., Agostinis-Sobrinho C., […], Demetriades C., […], Philippou E., Korolchuk VI., and Shannon OM., An expert consensus statement on biomarkers of ageing for use in intervention studies. The Journals of Gerontology: Series A.Jour 2024 December 21;glae297. doi:10.1093/gerona/glae297
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• Acharya A., and Demetriades C., mTORC1 activity licenses its own release from the lysosomal surface. Molecular Cell. 2024 October 31. doi:10.1016/j.molcel.2024.10.008
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• Fernandes SA., Angelidaki D-D., Nüchel J., Pan J., Gollwitzer P., Elkis Y., Artoni F., Wilhelm S., Kovacevic-Sarmiento M., and Demetriades C., Spatial and Functional Separation of mTORC1 Signaling in Response to Different Amino Acid Sources. Nature Cell Biology. 2024 October 9. doi:10.1038/s41556-024-01523-7
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• Priya A., Antoine-Bally S., Macé AS., Monteiro P., Sabatet V., Remy D., Dingli F., Loew D., Demetriades C., Gautreau AM., and Chavrier P., Codependencies of mTORC1 signaling and endolysosomal actin structures. Science Advances. 2023 September 13;eadd9084. 10.1126/sciadv.add9084
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• Nicastro R., Brohée L., Alba J., Nüchel J., Figlia G., Kipschull S., Gollwitzer P., Romero-Pozuelo J., Fernandes SA., Lamprakis A., Vanni S., Teleman AA., De Virgilio C., and Demetriades C., Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor. Nature Cell Biology. 2023 August 10. doi:10.1038/s41556-023-01198-6
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• Suzuki T, Chéret J, Scala FD, Akhundlu A, Gherardini J, Demetrius DL, O'Sullivan JDB, Kuka Epstein G, Bauman AJ, Demetriades C, Paus R. mTORC1 activity negatively regulates human hair follicle growth and pigmentation. EMBO Rep. 2023 Jul 5;24(7):e56574. doi: 10.15252/embr.202256574. Epub 2023 May 22. PMID: 37212043; PMCID: PMC10328083.
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• Artoni F., Grützmacher N., and Demetriades C., Unbiased Evaluation of Rapamycin’s Specificity as an mTOR Inhibitor. Aging Cell. 2023 May 24;e13888. doi:10.1111/acel.13888
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• Huang W., Kew C., Fernandes SA., Loerhke A., Han L., Demetriades C., and Antebi A., Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity. Nature Aging. 2022 Sept 19. doi:10.1038/s43587-022-00275-z
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• Gollwitzer P., Grützmacher N., Wilhelm S., Kümmel D., and Demetriades C., A Rag GTPase Dimer Code Defines the Regulation of mTORC1 by Amino Acids. Nature Cell Biology. 2022 Sept 12;24: 1394-1406. doi:10.1038/s41556-022-00976-y
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• Demetriades C, Nüchel J, Plomann M. GRASPing the unconventional secretory machinery to bridge cellular stress signaling to the extracellular proteome. Cell Stress. 2021 Oct 15;5(11):173-175. doi: 10.15698/cst2021.11.259. PMID: 34782889; PMCID: PMC8561302.
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• Fernandes SA, Demetriades C. The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging. Front Aging. 2021 Aug 27;2:707372. doi: 10.3389/fragi.2021.707372. PMID: 35822019; PMCID: PMC9261424.
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• Nüchel J, Tauber M, Nolte JL, Mörgelin M, Türk C, Eckes B, Demetriades C, Plomann M. An mTORC1-GRASP55 signaling axis controls unconventional secretion to reshape the extracellular proteome upon stress. Mol Cell. 2021 Aug 19;81(16):3275-3293.e12. doi: 10.1016/j.molcel.2021.06.017. Epub 2021 Jul 9. PMID: 34245671; PMCID: PMC8382303.
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• Fitzian K., Brückner A., Brohée L., Zech R., Antoni C., Kiontke S., Gasper R., Linard Matos AL., Beel S., Wilhelm S., Gerke V., Ungermann C., Nellist M., Raunser S., Demetriades C., Oeckinghaus A., and Kümmel D., TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation. Molecular Cell. 2021 Jul 1;81(13):2705-2721.e8. doi:10.1016/j.molcel.2021.04.019
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• Prentzell MT, Rehbein U, Cadena Sandoval M, De Meulemeester AS, Baumeister R, Brohée L, Berdel B, Bockwoldt M, Carroll B, Chowdhury SR, von Deimling A, Demetriades C, Figlia G; Genomics England Research Consortium; de Araujo MEG, Heberle AM, Heiland I, Holzwarth B, Huber LA, Jaworski J, Kedra M, Kern K, Kopach A, Korolchuk VI, van 't Land-Kuper I, Macias M, Nellist M, Palm W, Pusch S, Ramos Pittol JM, Reil M, Reintjes A, Reuter F, Sampson JR, Scheldeman C, Siekierska A, Stefan E, Teleman AA, Thomas LE, Torres-Quesada O, Trump S, West HD, de Witte P, Woltering S, Yordanov TE, Zmorzynska J, Opitz CA, Thedieck K. G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling. Cell. 2021 Feb 4;184(3):655-674.e27. doi: 10.1016/j.cell.2020.12.024. Epub 2021 Jan 25. PMID: 33497611; PMCID: PMC7868890.
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• Demetriades C., Doumpas N., and Teleman AA., Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell. 2014 February 13; 156(4):786-99. doi:10.1016/j.cell.2014.01.024
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