Role of Alix in miRNA packaging during extracellular vesicle biogenesis
Open accessAbstract
Evidence indicates that Alix, an accessory protein of the endosomal sorting complex required for transport (ESCRT), is involved in the biogenesis of extracellular vesicles (EVs). EVs contain selected patterns of microRNAs (miRNAs or miRs); however, little is known about the mechanisms of miRNA enrichment in EVs. The aim of the present study was to evaluate whether Alix is involved in the packaging of miRNAs within EVs released by human liver stem‑like cells (HLSCs). EVs released from HLSCs were enriched with miRNAs and expressed Alix and several RNA-binding proteins, including Argonaute 2 (Ago2), a member of the Argonaute family known to be involved in the transport and the processing of miRNAs. Co-immunoprecipitation experiments revealed an association between Alix and Ago2. The results from RT-qPCR indicated that in the Alix/Ago2 immunoprecipitates, miRNAs were detectable. EVs were instrumental in transferring selected miRNAs from HLSCs to human endothelial cells absent in the latter cells. Alix knockdown did not influence the number of EVs released by HLSCs, but it significantly decreased miRNA expression levels in the EVs and consequently their transfer to the endothelium. Our findings indicate that Alix binds to Ago2 and miRNAs, suggesting that it plays a key role in miRNA enrichment during EV biogenesis. These results may represent a novel function of Alix, demonstrating its involvement in the EV-mediated transfer of miRNAs.
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
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 involvement of Alix for EV release seems to occur only in muscle cells, as knockdown of Alix did not affect the number of ELVs released from human liver stem-like cells.
“Interestingly, the involvement of Alix for EV release seems to occur only in muscle cells as the knockdown of Alix did not affect the number of ELVs released from human liver stem-like cells (Iavello et al., 2016).”
From Skeletal Muscle-Released Extracellular Vesicles: State of the Art (2019) · cites this paper as Iavello et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007) · Nature Cell Biology · doi:10.1038/ncb1596 · Cited by 12,834 · see citing works
Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles
Colombo, M., Raposo, G., & Théry, C. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-101512-122326 · Cited by 6,186 · 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
Syndecan–syntenin–ALIX regulates the biogenesis of exosomes
Baietti, M. F., Zhang, Z., Mortier, E., Melchior, A., Degeest, G., Geeraerts, A., Ivarsson, Y., Depoortere, F., Coomans, C., Vermeiren, E., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2502 · Cited by 1,899 · see citing works
Shedding microvesicles: artefacts no more
Cocucci, E., Racchetti, G., & Meldolesi, J. (2009) · Trends in Cell Biology · doi:10.1016/j.tcb.2008.11.003 · Cited by 1,742 · see citing works
Ratajczak, J., Miękus, K., Kucia, M., Zhang, J., Reca, R., Dvořák, P., & Ratajczak, M. Z. (2006) · Leukemia · doi:10.1038/sj.leu.2404132 · Cited by 1,630 · see citing works
Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis
Dragovic, R., Gardiner, C., Brooks, A. S., Tannetta, D., Ferguson, D. J. P., Hole, P., Carr, B., Redman, C. W. G., Harris, A. L., Dobson, P. J., et al. (2011) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2011.04.003 · Cited by 1,368 · see citing works
Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A., & Ratajczak, M. Z. (2006) · Leukemia · doi:10.1038/sj.leu.2404296 · Cited by 1,340 · see citing works
The majority of microRNAs detectable in serum and saliva is concentrated in exosomes
Gallo, A., Tandon, M., Alevizos, I., & Illei, G. G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030679 · Cited by 1,060 · see citing works
Export of microRNAs and microRNA-protective protein by mammalian cells
Wang, K., Zhang, S., Weber, J., Baxter, D., & Galas, D. J. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq601 · Cited by 1,002 · see citing works
Anderson, P., & Kedersha, N. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200512082 · Cited by 984 · see citing works
Deregibus, M. C., Cantaluppi, V., Calogero, R., Iacono, M. L., Tetta, C., Biancone, L., Bruno, S., Bussolati, B., & Camussi, G. (2007) · Blood · doi:10.1182/blood-2007-03-078709 · Cited by 977 · see citing works
Self-citationAs we wait: coping with an imperfect nomenclature for extracellular vesicles
Gould, S. J., & Raposo, G. (2013) · Journal of Extracellular Vesicles · doi:10.3402/jev.v2i0.20389 · Cited by 864 · see citing works
AIP1/ALIX Is a Binding Partner for HIV-1 p6 and EIAV p9 Functioning in Virus Budding
Strack, B., Calistri, A., Craig, S., Popova, E., & Göttlinger, H. G. (2003) · Cell · doi:10.1016/s0092-8674(03)00653-6 · Cited by 825 · see citing works
Secreted microRNAs: a new form of intercellular communication
Chen, X., Liang, H., Zhang, J., Zen, K., & Zhang, C. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.12.001 · Cited by 761 · see citing works
Exosome mediated communication within the tumor microenvironment
Milane, L. S., Singh, A., Mattheolabakis, G., Suresh, M., & Amiji, M. M. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.06.029 · Cited by 738 · see citing works
Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis
Morita, E., Sandrin, V., Chung, H., Morham, S. G., Gygi, S. P., Rodesch, C. K., & Sundquist, W. I. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601850 · Cited by 724 · see citing works
Collino, F., Deregibus, M. C., Bruno, S., Sterpone, L., Aghemo, G., Viltono, L., Tetta, C., & Camussi, G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011803 · Cited by 608 · see citing works
Self-citationGhossoub, R., Lembo, F., Rubio, A., Baron, C. L., Bouchet, J., Vitale, N., Slavík, J., Machala, M., & Zimmermann, P. (2014) · Nature Communications · doi:10.1038/ncomms4477 · Cited by 601 · see citing works
Exosomes: Novel Biomarkers for Clinical Diagnosis
Jin, L., Li, J., Huang, B., Liu, J., Chen, X., Chen, X., Xu, Y., Huang, L., & Wang, X. (2015) · The Scientific World JOURNAL · doi:10.1155/2015/657086 · Cited by 567 · see citing works
Höck, J., & Meister, G. (2008) · Genome biology · doi:10.1186/gb-2008-9-2-210 · Cited by 564 · see citing works
Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane
Booth, A. M., Fang, Y., Fallon, J. K., Yang, J.-M., Hildreth, J. E. K., & Gould, S. J. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200508014 · Cited by 562 · see citing works
Exosomes: immune properties and potential clinical implementations
Chaput, N., & Théry, C. (2010) · Seminars in Immunopathology · doi:10.1007/s00281-010-0233-9 · Cited by 561 · see citing works
Virus budding and the ESCRT pathway
Votteler, J., & Sundquist, W. I. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.08.012 · Cited by 547 · see citing works
Lee, T. H., D’Asti, E., Magnus, N., Al-Nedawi, K. N. I., Meehan, B., & Rak, J. W. (2011) · Seminars in Immunopathology · doi:10.1007/s00281-011-0250-3 · Cited by 496 · see citing works
Isolation and Characterization of a Stem Cell Population from Adult Human Liver
Sanchez, M. B. H., Bruno, S., Buttiglieri, S., Tetta, C., Gatti, S., Deregibus, M. C., Bussolati, B., & Camussi, G. (2006) · Stem Cells · doi:10.1634/stemcells.2006-0114 · Cited by 411 · see citing works
Self-citationMartin‐Serrano, J., Yaravoy, A., Pérez-Caballero, D., & Bieniasz, P. D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2133846100 · Cited by 397 · see citing works
Higher-Order Oligomerization Targets Plasma Membrane Proteins and HIV Gag to Exosomes
Fang, Y., Wu, N., Gan, X., Yan, W., Morrell, J. C., & Gould, S. J. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050158 · Cited by 382 · see citing works
Extracellular Vesicles: Potential Roles in Regenerative Medicine
de Jong, O. G., van Balkom, B. W. M., Schiffelers, R. M., Bouten, C. V. C., & Verhaar, M. C. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00608 · Cited by 353 · see citing works
Heparanase activates the syndecan-syntenin-ALIX exosome pathway
Roucourt, B., Meeussen, S., Bao, J., Zimmermann, P., & David, G. (2015) · Cell Research · doi:10.1038/cr.2015.29 · Cited by 310 · see citing works
Human liver stem cell‐derived microvesicles accelerate hepatic regeneration in hepatectomized rats
Herrera, M. B., Fonsato, V., Gatti, S., Deregibus, M. C., Sordi, A., Cantarella, D., Calogero, R., Bussolati, B., Tetta, C., & Camussi, G. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00860.x · Cited by 309 · see citing works
Self-citationLopatina, T., Bruno, S., Tetta, C., Kalinina, N., Porta, M., & Camussi, G. (2014) · Cell Communication and Signaling · doi:10.1186/1478-811x-12-26 · Cited by 308 · see citing works
Self-citationProtein Targeting to Exosomes/Microvesicles by Plasma Membrane Anchors
Shen, B., Wu, N., Yang, J.-M., & Gould, S. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.208660 · Cited by 283 · see citing works
Missotten, M., Nichols, A., Rieger, K., & Sadoul, R. (1999) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400456 · Cited by 239 · see citing works
Argonaute 2 Complexes Selectively Protect the Circulating MicroRNAs in Cell-Secreted Microvesicles
Li, L., Zhu, D., Huang, L., Zhang, J., Bian, Z., Chen, X., Liu, Y., Zhang, C., & Zen, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046957 · Cited by 216 · see citing works
Bro1 is an endosome-associated protein that functions in the MVB pathway in Saccharomyces cerevisiae
Odorizzi, G., Katzmann, D. J., Babst, M., Audhya, A., & Emr, S. D. (2003) · Journal of Cell Science · doi:10.1242/jcs.00395 · Cited by 213 · see citing works
Fonsato, V., Collino, F., Sanchez, M. B. H., Cavallari, C., Deregibus, M. C., Cisterna, B., Bruno, S., Romagnoli, R., Salizzoni, M., Tetta, C., et al. (2012) · Stem Cells · doi:10.1002/stem.1161 · Cited by 200 · see citing works
Self-citationRole of extracellular RNA-carrying vesicles in cell differentiation and reprogramming
Quesenberry, P. J., Aliotta, J. M., Deregibus, M. C., & Camussi, G. (2015) · Stem Cell Research & Therapy · doi:10.1186/s13287-015-0150-x · Cited by 194 · see citing works
Self-citationAliotta, J. M., Sanchez-Guijo, F. M., Dooner, G. J., Johnson, K. W., Dooner, M. S., Greer, K., Greer, D. A., Pimentel, J., Kolankiewicz, L. M., Puente, N. A., et al. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0128 · Cited by 180 · see citing works
Self-citationKatoh, M. (2013) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2013.1444 · Cited by 156 · see citing works
Alix/AIP1 Antagonizes Epidermal Growth Factor Receptor Downregulation by the Cbl-SETA/CIN85 Complex
Schmidt, M. H. H., Hoeller, D., Yu, J., Furnari, F. B., Cavenee, W. K., Đikić, I., & Bögler, O. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.20.8981-8993.2004 · Cited by 121 · see citing works
Deregibus, M. C., Buttiglieri, S., Russo, S., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300711200 · Cited by 101 · see citing works
Self-citationHuman liver stem cells improve liver injury in a model of fulminant liver failure
Sanchez, M. B. H., Fonsato, V., Bruno, S., Grange, C., Gilbo, N., Romagnoli, R., Tetta, C., & Camussi, G. (2012) · Hepatology · doi:10.1002/hep.25986 · Cited by 92 · see citing works
Self-citationLaver, J. D., Li, X., Ancevicius, K., Westwood, J. T., Smibert, C. A., Morris, Q., & Lipshitz, H. D. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt702 · Cited by 81 · see citing works
Cellular Phenotype and Extracellular Vesicles: Basic and Clinical Considerations
Quesenberry, P. J., Goldberg, L. R., Aliotta, J. M., et al. (2014) · Stem Cells and Development · doi:10.1089/scd.2013.0594 · Cited by 80 · see citing works
Self-citationRNA Recognition and Stress Granule Formation by TIA Proteins
Waris, S., Wilce, M. C. J., & Wilce, J. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151223377 · Cited by 73 · see citing works
Involvement of the Conserved Adaptor Protein Alix in Actin Cytoskeleton Assembly
Pan, S., Wang, R., Zhou, X., He, G., Koomen, J. M., Kobayashi, R., Sun, L., Corvera, J., Gallick, G. E., & Kuang, J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602263200 · Cited by 68 · see citing works
Roxrud, I., Stenmark, H., & Malerød, L. (2010) · Biology of the Cell · doi:10.1042/bc20090161 · Cited by 61 · see citing works
Human prion protein binds Argonaute and promotes accumulation of microRNA effector complexes
Gibbings, D., Leblanc, P., Jay, F., et al. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2273 · Cited by 51 · see citing works
Morita, E. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08534.x · Cited by 42 · see citing works
Identification of the HIV-1 NC Binding Interface in Alix Bro1 Reveals a Role for RNA
Sette, P., Dussupt, V., & Bouamr, F. (2012) · Journal of Virology · doi:10.1128/jvi.01260-12 · Cited by 38 · see citing works
Wu (2010) · International Journal of Molecular Medicine · doi:10.3892/ijmm_00000393 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
RNA delivery by extracellular vesicles in mammalian cells and its applications
O’Brien, K., Breyne, K., Ughetto, S., Laurent, L. C., & Breakefield, X. O. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0251-y · Cited by 1,811 · see citing works
Regulation of exosome production and cargo sorting
Wei, H., Chen, Q., Lin, L., Sha, C., Li, T., Liu, Y., Yin, X., Xu, Y., Chen, L., Gao, W., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.53671 · Cited by 385 · see citing works
Skeletal Muscle-Released Extracellular Vesicles: State of the Art
Rome, S., Forterre, A., Mizgier, M. L., & Bouzakri, K. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00929 · Cited by 139 · see citing works
- Authors
- IAVELLO, A., FRECH, V. S. L., GAI, C., DEREGIBUS, M. C., QUESENBERRY, P. J., & CAMUSSI, G.
- Affiliations
- University of Turin (IT)
- Brown University (US)
- Corresponding author
- CAMUSSI, GIOVANNI
- Venue
- International Journal of Molecular Medicine
- Publisher
- Spandidos Publications
- Published
- 2016-02-12
- Volume
- 37
- Issue
- 4
- Pages
- 958-966
- ISSN
- 1107-3756 (ISSN-L)
- 1791-244X
- PMC
- PMC4790646
- OpenAlex
- W2259035271
- Cited by
- 175
- References
- 52
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 25 · 2023: 20 · 2022: 15 · 2021: 19 · 2020: 24 · 2019: 13 · 2018: 7 · 2017: 18 · 2016: 3
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- International Journal of Molecular Medicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Associazione Italiana per la Ricerca sul Cancro (12890, IG 12890)
- National Institutes of Health (UH2TR000880, UH3TR000880)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Alix, extracellular vesicles, extracellular vesicle biogenesis, Argonaute 2, ESCRT, endothelial cells, protein-protein interaction
- MeSH terms
- Extracellular Vesicles, Calcium-Binding Proteins, Cell Line, Gene Expression Regulation, Humans, Liver, Stem Cells, Cell Cycle Proteins, Hepatocytes, MicroRNAs, Immunoprecipitation, Gene Knockdown Techniques, Endosomal Sorting Complexes Required for Transport, Argonaute Proteins, Human Umbilical Vein Endothelial Cells
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
