Extracellular vesicles are independent metabolic units with asparaginase activity
Open accessAbstract
Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC)-derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1). Critically, we show that Asrgl1 activity is selective for asparagine and is devoid of glutaminase activity. We found that mouse and human NSC EVs traffic Asrgl1. Our results demonstrate, for the first time, that NSC EVs function as independent metabolic units that are able to modify the concentrations of critical nutrients, with the potential to affect the physiology of their microenvironment.
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sEVs can have intrinsic metabolic activity.
“It has previously been reported that sEVs can have intrinsic metabolic activity (Iraci et al., 2017, Peruzzotti-Jametti et al., 2018, Yoshida et al., 2019).”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Iraci et al., 2017
EVs have asparaginase and succinase activity to suppress neuroinflammation.
“EVs have been shown to have asparaginase and succinase activity to suppress neuroinflammation (Iraci et al., 2017, Peruzzotti-Jametti et al., 2018)”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Iraci et al., 2017
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Cites
Extracellular vesicles: Exosomes, microvesicles, and friends
Raposo, G., & Stoorvogel, W. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201211138 · Cited by 8,099 · see citing works
Membrane vesicles as conveyors of immune responses
Théry, C., Ostrowski, M., & Segura, É. (2009) · Nature reviews. Immunology · doi:10.1038/nri2567 · Cited by 3,869 · see citing works
Communication by Extracellular Vesicles: Where We Are and Where We Need to Go
Tkach, M., & Théry, C. (2016) · Cell · doi:10.1016/j.cell.2016.01.043 · Cited by 3,444 · see citing works
Witwer, K. W., Buzás, E. I., Bemis, L., Bora, A., Lässer, C., Lötvall, J. O., Hoen, E. N. M. N., Piper, M. G., Sivaraman, S., Skog, J., et al. (2013) · Journal of Extracellular Vesicles · doi:10.3402/jev.v2i0.20360 · Cited by 2,424 · see citing works
Optimized exosome isolation protocol for cell culture supernatant and human plasma
Lobb, R. J., Becker, M., Wen, S., Wong, C. S. F., Wiegmans, A. P., Leimgruber, A., & Möller, A. (2015) · Journal of Extracellular Vesicles · doi:10.3402/jev.v4.27031 · Cited by 1,725 · see citing works
The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma
Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., et al. (2009) · Cell Cycle · doi:10.4161/cc.8.23.10238 · Cited by 1,391 · see citing works
Birsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M. (2015) · Cell · doi:10.1016/j.cell.2015.07.016 · Cited by 1,388 · see citing works
Vesiclepedia: A Compendium for Extracellular Vesicles with Continuous Community Annotation
Kalra, H., Simpson, R. J., Ji, H., Aikawa, E., Altevogt, P., Askenase, P., Bond, V. C., Borràs, F. E., Breakefield, X., Budnik, V., et al. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001450 · Cited by 1,367 · see citing works
Self-citationSupporting aspartate biosynthesis is an essential function of respiration in proliferating cells
Sullivan, L. B., Gui, D. Y., Hosios, A. M., Bush, L. N., Freinkman, E., & Vander Heiden, M. G. (2015) · Cell · doi:10.1016/j.cell.2015.07.017 · Cited by 1,173 · see citing works
Molecular Characterization of Dendritic Cell-Derived Exosomes
Théry, C., Régnault, A., Garin, J., Wolfers, J., Zitvogel, L., Ricciardi‐Castagnoli, P., Raposo, G., & Amigorena, S. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.147.3.599 · Cited by 1,065 · see citing works
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J. C., Tudawe, T., Seviour, E. G., San Lucas, F. A., et al. (2016) · eLife · doi:10.7554/elife.10250 · Cited by 927 · see citing works
Haas, R., Smith, J., Rocher-Ros, V., Nadkarni, S., Montero‐Melendez, T., D’Acquisto, F., Bland, E. J., Bombardieri, M., Pitzalis, C., Perretti, M., et al. (2015) · PLoS Biology · doi:10.1371/journal.pbio.1002202 · Cited by 782 · see citing works
Deatherage, B. L., & Cookson, B. T. (2012) · Infection and Immunity · doi:10.1128/iai.06014-11 · Cited by 765 · see citing works
Book Review: GABA and Glutamate in the Human Brain
Petroff, O. A. C. (2002) · The Neuroscientist · doi:10.1177/1073858402238515 · Cited by 678 · see citing works
Exosomes: Vehicles of Intercellular Signaling, Biomarkers, and Vectors of Cell Therapy
Kourembanas, S. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021014-071641 · Cited by 655 · see citing works
Sonveaux, P., Copetti, T., De Saedeleer, C. J., Végran, F., Verrax, J., Kennedy, K. M., Moon, E. J., Dhup, S., Danhier, P., Frérart, F., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033418 · Cited by 536 · see citing works
Duval, M. (2002) · Blood · doi:10.1182/blood.v99.8.2734 · Cited by 409 · see citing works
Minciacchi, V. R., You, S., Spinelli, C., Morley, S., Zandian, M., Aspuria, P.-J. P., Cavallini, L., Ciardiello, C., Reis-Sobreiro, M., Morello, M., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3598 · Cited by 403 · see citing works
Poliakov, A., Spilman, M. S., Dokland, T., et al. (2008) · The Prostate · doi:10.1002/pros.20860 · Cited by 325 · see citing works
Cossetti, C., Iraci, N., Mercer, T. R., Leonardi, T., Alpi, E., Drago, D., Alfaro‐Cervelló, C., Saini, H. K., Davis, M. P. A., Schaeffer, J., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.020 · Cited by 301 · see citing works
Self-citationExosomes as divine messengers: are they the Hermes of modern molecular oncology?
Braicu, C., Tomuleasa, C., Monroig-Bosque, P. D. C., Cucuianu, A., Berindan‐Neagoe, I., & Călin, G. A. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.130 · Cited by 296 · see citing works
Amino acid regulation of gene expression
Fafournoux, P., Bruhat, A., & Jousse, C. (2000) · Biochemical Journal · doi:10.1042/0264-6021:3510001 · Cited by 265 · see citing works
Human neural stem cell transplantation in ALS: initial results from a phase I trial
Mazzini, L., Gelati, M., Profico, D. C., Sgaravizzi, G., Pensi, M. P., Muzi, G., Ricciolini, C., Nodari, L. R., Carletti, S., Giorgi, C., et al. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-014-0371-2 · Cited by 206 · see citing works
Self-citationAccurate calculation of the density of proteins
Quillin, M. L., & Matthews, B. W. (2000) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s090744490000679x · Cited by 201 · see citing works
Amino acid regulation of gene expression
Fafournoux, P., Bruhat, A., & Jousse, C. (2000) · Biochemical Journal · doi:10.1042/bj3510001 · Cited by 193 · see citing works
García, N. A., Moncayo, J., Sepúlveda, P., & Díez‐Juan, A. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv260 · Cited by 185 · see citing works
Glutamate and its receptors in cancer
Stepulak, A., Rola, R., Polberg, K., & Ikonomidou, C. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1182-6 · Cited by 171 · see citing works
MicroRNA transport: A new way in cell communication
Xu, L., Yang, B., & Ai, J. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24344 · Cited by 138 · see citing works
Ollenschläger, G., Roth, E., Linkesch, W., JANSEN, S., Simmel, A., & Mödder, B. (1988) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.1988.tb01049.x · Cited by 134 · see citing works
EVpedia: A community web resource for prokaryotic and eukaryotic extracellular vesicles research
Kim, D., Lee, J., Simpson, R. J., et al. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.02.005 · Cited by 120 · see citing works
The Human Asparaginase-like Protein 1 hASRGL1 Is an Ntn Hydrolase with β-Aspartyl Peptidase Activity
Cantor, J. R., Stone, E. M., Chantranupong, L., & Georgiou, G. (2009) · Biochemistry · doi:10.1021/bi901397h · Cited by 83 · see citing works
Gamma-aminobutyric acid (GABA) and cell proliferation: focus on cancer cells.
Watanabe, M., Maemura, K., Oki, K., Shiraishi, N., Shibayama, Y., & Katsu, K. (2006) · PubMed · doi:10.14670/hh-21.1135 · Cited by 79 · see citing works
Johnson, S. M., Dempsey, C. E., Chadwick, A. L., et al. (2016) · Blood · doi:10.1182/blood-2015-12-688051 · Cited by 66 · see citing works
Karpel‐Massler, G., Ramani, D., Shu, C., Halatsch, M., Westhoff, M., Bruce, J. N., Canoll, P., & Siegelin, M. D. (2016) · Oncotarget · doi:10.18632/oncotarget.9257 · Cited by 59 · see citing works
Human prostasomes express glycolytic enzymes with capacity for ATP production
Ronquist, G. K., Ek, B., Stavreus-Evers, A. C., Larsson, A. O., & Ronquist, G. (2013) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00511.2012 · Cited by 56 · see citing works
A novel asparaginase‐like protein is a sperm autoantigen in rats
Bush, L. A., Herr, J. C., Wolkowicz, M. J., et al. (2002) · Molecular Reproduction and Development · doi:10.1002/mrd.10092 · Cited by 39 · see citing works
Regulation of amino acid transporters by amino acid availability
Christie, G. R., Hyde, R., & Hundal, H. S. (2001) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/00075197-200109000-00014 · Cited by 24 · see citing works
Viral Manipulation of Neural Stem/Precursor Cells
Iraci, N., Tyzack, G. E., Cossetti, C., Alfaro‐Cervelló, C., & Pluchino, S. (2013) · Neuromethods · doi:10.1007/978-1-62703-610-8_14 · Cited by 1 · see citing works
Self-citation
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- [25]Zhao H Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism Elife 2016 5 e10250 26920219 PMC4841778
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Rong, Y., Liu, W., Wang, J., Fan, J., Luo, Y., Li, L., Kong, F., Chen, J., Tang, P., & Cai, W. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-1571-8 · Cited by 333 · see citing works
Neural stem cells traffic functional mitochondria via extracellular vesicles
Peruzzotti-Jametti, L., Bernstock, J. D., Willis, C. M., Manferrari, G., Rogall, R., Fernandez-Vizarra, E., Williamson, J. C., Braga, A., van den Bosch, A., Leonardi, T., et al. (2021) · PLOS Biology · doi:10.1371/journal.pbio.3001166 · Cited by 263 · see citing works
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Fafián-Labora, J. A., Rodríguez-Navarro, J. A., & O’Loghlen, A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.004 · Cited by 203 · see citing works
Zhong, L., Wang, J., Wang, P., Liu, X., Liu, P., Cheng, X., Cao, L., Wu, H., Chen, J., & Zhou, L. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03409-1 · Cited by 110 · see citing works
Extracellular Vesicles as an Emerging Frontier in Spinal Cord Injury Pathobiology and Therapy
Dutta, D., Khan, N., Wu, J., & Jay, S. M. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.01.003 · Cited by 112 · see citing works
Extracellular Vesicles as Novel Diagnostic and Prognostic Biomarkers for Parkinson’s Disease
Leggio, L., Paternò, G., Vivarelli, S., Falzone, G. G., Giachino, C., Marchetti, B., & Iraci, N. (2021) · Aging and disease · doi:10.14336/ad.2021.0527 · Cited by 55 · see citing works
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- Authors
- Iraci, N., Gaude, E., Leonardi, T., Costa, A. S. H., Cossetti, C., Peruzzotti-Jametti, L., Bernstock, J. D., Saini, H. K., Gelati, M., Vescovi, A. L., Bastos, C., Faria, N., Occhipinti, L. G., Enright, A. J., Frezza, C., & Pluchino, S.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- European Bioinformatics Institute (GB)
- National Institutes of Health (US)
- Casa Sollievo della Sofferenza (IT)
- MRC Elsie Widdowson Laboratory (GB)
- Corresponding author
- Frezza, Christian
- Pluchino, Stefano
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2017-07-03
- Volume
- 13
- Issue
- 9
- Pages
- 951-955
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5563455
- OpenAlex
- W2726430797
- Cited by
- 134
- References
- 38
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 13 · 2023: 16 · 2022: 20 · 2021: 17 · 2020: 14 · 2019: 16 · 2018: 17 · 2017: 5
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Cambridge University Engineering Department Publications Database (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust
- Medical Research Council (MR/K026682/1, MC_PC_12009, MR/R005699/1, MC_UU_12022/6)
- Engineering and Physical Sciences Research Council (EP/K03099X/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- extracellular vesicles, neural stem/progenitor cells, asparagine metabolism, glutaminase activity, nutrient exchange, microenvironment, metabolomics
- MeSH terms
- Extracellular Vesicles, Asparaginase, Models, Biological
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