Skip to main content

Advertisement

Log in

Inside(sight) of tiny communicator: exosome biogenesis, secretion, and uptake

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Discovered in the late 1980s as an extracellular vesicle of endosomal origin secreted from reticulocytes, exosomes recently gained scientific attention due to its role in intercellular communication. Exosomes have now been identified to carry cell-specific cargo of nucleic acids, proteins, lipids, and other biologically active molecules. Exosomes can be selectively taken up by neighboring or distant cells, which has shown to result in structural and functional responses in the recipient cells. Recent advances indicate the regulation of exosomes at various steps, including their biogenesis, selection of their cargo, as well as cell-specific uptake. This review will shed light on the differences between the type of extracellular vesicles. In this review, we discuss the recent progress in our understanding of the regulation of exosome biogenesis, secretion, and uptake.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13:269–288

    Article  CAS  PubMed  Google Scholar 

  2. Burnier L, Fontana P, Kwak BR, Angelillo-Scherrer A (2009) Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 101:439–451

    Article  CAS  PubMed  Google Scholar 

  3. Boilard E, Blanco P, Nigrovic PA (2012) Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol 8:534–542. https://doi.org/10.1038/nrrheum.2012.118

    Article  CAS  PubMed  Google Scholar 

  4. Smalley DM, Sheman NE, Nelson K, Theodorescu D (2008) Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. J Proteome Res 7:2088–2096. https://doi.org/10.1021/pr700775x

    Article  CAS  PubMed  Google Scholar 

  5. Zachau AC, Landen M, Mobarrez F, Nybom R, Wallen H, Wetterberg L (2012) Leukocyte-derived microparticles and scanning electron microscopic structures in two fractions of fresh cerebrospinal fluid in amyotrophic lateral sclerosis: a case report. J Med Case Rep 6:274. https://doi.org/10.1186/1752-1947-6-274

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chaput N, Thery C (2011) Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 33:419–440. https://doi.org/10.1007/s00281-010-0233-9

    Article  CAS  PubMed  Google Scholar 

  7. Record M, Subra C, Silvente-Poirot S, Poirot M (2011) Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol 81:1171–1182. https://doi.org/10.1016/j.bcp.2011.02.011

    Article  CAS  PubMed  Google Scholar 

  8. Kajimoto T, Okada T, Miya S, Zhang L, Nakamura S (2013) Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes. Nat Commun 4:2712. https://doi.org/10.1038/ncomms3712

    Article  CAS  PubMed  Google Scholar 

  9. Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107:1047–1057. https://doi.org/10.1161/CIRCRESAHA.110.226456

    Article  CAS  PubMed  Google Scholar 

  10. Lynch SF, Ludlam CA (2007) Plasma microparticles and vascular disorders. Br J Haematol 137:36–48. https://doi.org/10.1111/j.1365-2141.2007.06514.x

    Article  CAS  PubMed  Google Scholar 

  11. Meziani F, Tesse A, Andriantsitohaina R (2008) Microparticles are vectors of paradoxical information in vascular cells including the endothelium: role in health and diseases. Pharmacol Rep 60:75–84

    CAS  PubMed  Google Scholar 

  12. Chironi GN, Boulanger CM, Simon A, Dignat-George F, Freyssinet JM, Tedgui A (2009) Endothelial microparticles in diseases. Cell Tissue Res 335:143–151. https://doi.org/10.1007/s00441-008-0710-9

    Article  PubMed  Google Scholar 

  13. Boulanger CM, Amabile N, Tedgui A (2006) Circulating microparticles: a potential prognostic marker for atherosclerotic vascular disease. Hypertension 48:180–186. https://doi.org/10.1161/01.HYP.0000231507.00962.b5

    Article  CAS  PubMed  Google Scholar 

  14. Tan KT, Lip GY (2005) The potential role of platelet microparticles in atherosclerosis. Thromb Haemost 94:488–492. https://doi.org/10.1160/th05-03-0201

    Article  CAS  PubMed  Google Scholar 

  15. Dey-Hazra E, Hertel B, Kirsch T, Woywodt A, Lovric S, Haller H, Haubitz M, Erdbruegger U (2010) Detection of circulating microparticles by flow cytometry: influence of centrifugation, filtration of buffer, and freezing. Vasc Health Risk Manag 6:1125–1133. https://doi.org/10.2147/VHRM.S13236

    Article  PubMed  PubMed Central  Google Scholar 

  16. VanWijk MJ, Nieuwland R, Boer K, van der Post JA, VanBavel E, Sturk A (2002) Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction? Am J Obstet Gynecol 187:450–456

    Article  PubMed  Google Scholar 

  17. Herring JM, McMichael MA, Smith SA (2013) Microparticles in health and disease. J Vet Intern Med 27:1020–1033. https://doi.org/10.1111/jvim.12128

    Article  CAS  PubMed  Google Scholar 

  18. Roos MA, Gennero L, Denysenko T, Reguzzi S, Cavallo G, Pescarmona GP, Ponzetto A (2010) Microparticles in physiological and in pathological conditions. Cell Biochem Funct 28:539–548. https://doi.org/10.1002/cbf.1695

    Article  CAS  PubMed  Google Scholar 

  19. Patil R, Ghosh K, Satoskar P, Shetty S (2013) Elevated procoagulant endothelial and tissue factor expressing microparticles in women with recurrent pregnancy loss. PLoS ONE 8:e81407. https://doi.org/10.1371/journal.pone.0081407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jadli A, Ghosh K, Satoskar P, Damania K, Bansal V, Shetty S (2017) Combination of copeptin, placental growth factor and total annexin V microparticles for prediction of preeclampsia at 10–14 weeks of gestation. Placenta 58:67–73. https://doi.org/10.1016/j.placenta.2017.08.009

    Article  CAS  PubMed  Google Scholar 

  21. Badimon L, Suades R, Arderiu G, Pena E, Chiva-Blanch G, Padro T (2017) Microvesicles in atherosclerosis and angiogenesis: from bench to bedside and reverse. Front Cardiovasc Med 4:77. https://doi.org/10.3389/fcvm.2017.00077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gomez I, Ward B, Souilhol C, Recarti C, Ariaans M, Johnston J, Burnett A, Mahmoud M, Luong LA, West L, Long M, Parry S, Woods R, Hulston C, Benedikter B, Niespolo C, Bazaz R, Francis S, Kiss-Toth E, van Zandvoort M, Schober A, Hellewell P, Evans PC, Ridger V (2020) Neutrophil microvesicles drive atherosclerosis by delivering miR-155 to atheroprone endothelium. Nat Commun 11:214. https://doi.org/10.1038/s41467-019-14043-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Y, Xie Y, Zhang A, Wang M, Fang Z, Zhang J (2019) Exosomes: an emerging factor in atherosclerosis. Biomed Pharmacother 115:108951. https://doi.org/10.1016/j.biopha.2019.108951

    Article  CAS  PubMed  Google Scholar 

  24. Chiva-Blanch G, Padro T, Alonso R, Crespo J, Perez de Isla L, Mata P, Badimon L (2019) Liquid biopsy of extracellular microvesicles maps coronary calcification and atherosclerotic plaque in asymptomatic patients with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 39:945–955. https://doi.org/10.1161/ATVBAHA.118.312414

    Article  CAS  PubMed  Google Scholar 

  25. Rosinska J, Ambrosius W, Maciejewska J, Narozny R, Kozubski W, Lukasik M (2019) Association of platelet-derived microvesicles and their phenotypes with carotid atherosclerosis and recurrent vascular events in patients after ischemic stroke. Thromb Res 176:18–26. https://doi.org/10.1016/j.thromres.2019.01.014

    Article  CAS  PubMed  Google Scholar 

  26. Kovacs AF, Lang O, Turiak L, Acs A, Kohidai L, Fekete N, Alasztics B, Meszaros T, Buzas EI, Rigo J Jr, Pallinger E (2018) The impact of circulating preeclampsia-associated extracellular vesicles on the migratory activity and phenotype of THP-1 monocytic cells. Sci Rep 8:5426. https://doi.org/10.1038/s41598-018-23706-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dini L, Tacconi S, Carata E, Tata AM, Vergallo C, Panzarini E (2020) Microvesicles and exosomes in metabolic diseases and inflammation. Cytokine Growth Factor Rev 777:777. https://doi.org/10.1016/j.cytogfr.2019.12.008

    Article  CAS  Google Scholar 

  28. Chiva-Blanch G, Badimon L (2019) Cross-talk between lipoproteins and inflammation: the role of microvesicles. J Clin Med 8:777. https://doi.org/10.3390/jcm8122059

    Article  Google Scholar 

  29. Lv Y, Tan J, Miao Y, Zhang Q (2019) The role of microvesicles and its active molecules in regulating cellular biology. J Cell Mol Med 23:7894–7904. https://doi.org/10.1111/jcmm.14667

    Article  PubMed  PubMed Central  Google Scholar 

  30. Stahl PD, Raposo G (2019) Extracellular vesicles: exosomes and microvesicles, integrators of homeostasis. Physiology 34:169–177. https://doi.org/10.1152/physiol.00045.2018

    Article  CAS  PubMed  Google Scholar 

  31. Agrahari V, Agrahari V, Burnouf PA, Chew CH, Burnouf T (2019) Extracellular microvesicles as new industrial therapeutic frontiers. Trends Biotechnol 37:707–729. https://doi.org/10.1016/j.tibtech.2018.11.012

    Article  CAS  PubMed  Google Scholar 

  32. Sedgwick AE, D'Souza-Schorey C (2018) The biology of extracellular microvesicles. Traffic 19:319–327. https://doi.org/10.1111/tra.12558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Oerlemans MI, Koudstaal S, Chamuleau SA, de Kleijn DP, Doevendans PA, Sluijter JP (2013) Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection. Int J Cardiol 165:410–422. https://doi.org/10.1016/j.ijcard.2012.03.055

    Article  PubMed  Google Scholar 

  34. Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345. https://doi.org/10.1038/35070009

    Article  CAS  PubMed  Google Scholar 

  35. Gyorgy B, Szabo TG, Pasztoi M, Pal Z, Misjak P, Aradi B, Laszlo V, Pallinger E, Pap E, Kittel A, Nagy G, Falus A, Buzas EI (2011) Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cell Mol Life Sci 68:2667–2688. https://doi.org/10.1007/s00018-011-0689-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dignat-George F, Boulanger CM (2011) The many faces of endothelial microparticles. Arterioscler Thromb Vasc Biol 31:27–33. https://doi.org/10.1161/ATVBAHA.110.218123

    Article  CAS  PubMed  Google Scholar 

  37. Orlando KA, Stone NL, Pittman RN (2006) Rho kinase regulates fragmentation and phagocytosis of apoptotic cells. Exp Cell Res 312:5–15. https://doi.org/10.1016/j.yexcr.2005.09.012

    Article  CAS  PubMed  Google Scholar 

  38. Wickman GR, Julian L, Mardilovich K, Schumacher S, Munro J, Rath N, Zander SA, Mleczak A, Sumpton D, Morrice N, Bienvenut WV, Olson MF (2013) Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ 20:1293–1305. https://doi.org/10.1038/cdd.2013.69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz AL, Holmgren L (2001) Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci USA 98:6407–6411. https://doi.org/10.1073/pnas.101129998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Holmgren L, Szeles A, Rajnavolgyi E, Folkman J, Klein G, Ernberg I, Falk KI (1999) Horizontal transfer of DNA by the uptake of apoptotic bodies. Blood 93:3956–3963

    Article  CAS  PubMed  Google Scholar 

  41. Savill J, Dransfield I, Gregory C, Haslett C (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965–975. https://doi.org/10.1038/nri957

    Article  CAS  PubMed  Google Scholar 

  42. Akers JC, Gonda D, Kim R, Carter BS, Chen CC (2013) Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol 113:1–11. https://doi.org/10.1007/s11060-013-1084-8

    Article  PubMed  PubMed Central  Google Scholar 

  43. Trams EG, Lauter CJ, Salem N Jr, Heine U (1981) Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 645:63–70

    Article  CAS  PubMed  Google Scholar 

  44. Johnstone RM (2005) Revisiting the road to the discovery of exosomes. Blood Cells Mol Dis 34:214–219. https://doi.org/10.1016/j.bcmd.2005.03.002

    Article  CAS  PubMed  Google Scholar 

  45. Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97:329–393

    Article  CAS  PubMed  Google Scholar 

  46. Pan BT, Teng K, Wu C, Adam M, Johnstone RM (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948

    Article  CAS  PubMed  Google Scholar 

  47. Anitei M, Wassmer T, Stange C, Hoflack B (2010) Bidirectional transport between the trans-Golgi network and the endosomal system. Mol Membr Biol 27:443–456. https://doi.org/10.3109/09687688.2010.522601

    Article  CAS  PubMed  Google Scholar 

  48. Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73:1907–1920. https://doi.org/10.1016/j.jprot.2010.06.006

    Article  CAS  PubMed  Google Scholar 

  49. Simpson RJ, Jensen SS, Lim JW (2008) Proteomic profiling of exosomes: current perspectives. Proteomics 8:4083–4099. https://doi.org/10.1002/pmic.200800109

    Article  CAS  PubMed  Google Scholar 

  50. Ailawadi S, Wang X, Gu H, Fan GC (2015) Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta 1852:1–11. https://doi.org/10.1016/j.bbadis.2014.10.008

    Article  CAS  PubMed  Google Scholar 

  51. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30; sup pp 1–13. https://doi.org/10.1038/ncb2000

  52. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, De Medina P, Monsarrat B, Perret B, Silvente-Poirot S, Poirot M, Record M (2010) Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res 51:2105–2120. https://doi.org/10.1194/jlr.M003657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD, Wurdinger T, Middeldorp JM (2010) Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA 107:6328–6333. https://doi.org/10.1073/pnas.0914843107

    Article  PubMed  PubMed Central  Google Scholar 

  54. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172

    Article  CAS  PubMed  Google Scholar 

  55. Hoefer IE, Piek JJ, Pasterkamp G (2006) Pharmaceutical interventions to influence arteriogenesis: new concepts to treat ischemic heart disease. Curr Med Chem 13:979–987

    Article  CAS  PubMed  Google Scholar 

  56. Sluijter JPG (2013) MicroRNAs in cardiovascular regenerative medicine: directing tissue repair and cellular differentiation. ISRN Vasc Med 2013:1–16. https://doi.org/10.1155/2013/593517

    Article  CAS  Google Scholar 

  57. Zhou J, Li YS, Nguyen P, Wang KC, Weiss A, Kuo YC, Chiu JJ, Shyy JY, Chien S (2013) Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress. Circ Res 113:40–51. https://doi.org/10.1161/CIRCRESAHA.113.280883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, Hristov M, Koppel T, Jahantigh MN, Lutgens E, Wang S, Olson EN, Schober A, Weber C (2009) Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal 2:ra81. https://doi.org/10.1126/scisignal.2000610

    Article  PubMed  Google Scholar 

  59. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. https://doi.org/10.1038/ncb1596

    Article  CAS  PubMed  Google Scholar 

  60. Dassler-Plenker J, Kuttner V (1873) Egeblad M (2020) Communication in tiny packages: Exosomes as means of tumor-stroma communication. Biochim Biophys Acta Rev Cancer 2:188340. https://doi.org/10.1016/j.bbcan.2020.188340

    Article  CAS  Google Scholar 

  61. Hough KP, Trevor JL, Strenkowski JG, Wang Y, Chacko BK, Tousif S, Chanda D, Steele C, Antony VB, Dokland T, Ouyang X, Zhang J, Duncan SR, Thannickal VJ, Darley-Usmar VM, Deshane JS (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54–64. https://doi.org/10.1016/j.redox.2018.06.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Pourhanifeh MH, Mahjoubin-Tehran M, Shafiee A, Hajighadimi S, Moradizarmehri S, Mirzaei H, Asemi Z (2019) MicroRNAs and exosomes: small molecules with big actions in multiple myeloma pathogenesis. IUBMB Life 777:777. https://doi.org/10.1002/iub.2211

    Article  CAS  Google Scholar 

  63. Wang J, Ni J, Beretov J, Thompson J, Graham P, Li Y (2019) Exosomal microRNAs as liquid biopsy biomarkers in prostate cancer. Crit Rev Oncol Hematol 145:102860. https://doi.org/10.1016/j.critrevonc.2019.102860

    Article  PubMed  Google Scholar 

  64. Yang F, Ning Z, Ma L, Liu W, Shao C, Shu Y, Shen H (2017) Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts. Mol Cancer 16:148. https://doi.org/10.1186/s12943-017-0718-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhang J, Li S, Li L, Li M, Guo C, Yao J, Mi S (2015) Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinform 13:17–24. https://doi.org/10.1016/j.gpb.2015.02.001

    Article  CAS  Google Scholar 

  66. Mathiyalagan P, Liang Y, Kim D, Misener S, Thorne T, Kamide CE, Klyachko E, Losordo DW, Hajjar RJ, Sahoo S (2017) Angiogenic mechanisms of human CD34(+) stem cell exosomes in the repair of ischemic hindlimb. Circ Res 120:1466–1476. https://doi.org/10.1161/CIRCRESAHA.116.310557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yao Y, Sun W, Sun Q, Jing B, Liu S, Liu X, Shen G, Chen R, Wang H (2019) Platelet-derived exosomal MicroRNA-25-3p inhibits coronary vascular endothelial cell inflammation through adam10 via the NF-kappaB signaling pathway in ApoE(−/−) mice. Front Immunol 10:2205. https://doi.org/10.3389/fimmu.2019.02205

    Article  PubMed  PubMed Central  Google Scholar 

  68. Zhu J, Liu B, Wang Z, Wang D, Ni H, Zhang L, Wang Y (2019) Exosomes from nicotine-stimulated macrophages accelerate atherosclerosis through miR-21-3p/PTEN-mediated VSMC migration and proliferation. Theranostics 9:6901–6919. https://doi.org/10.7150/thno.37357

    Article  PubMed  PubMed Central  Google Scholar 

  69. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G (2012) Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol 14:677–685. https://doi.org/10.1038/ncb2502

    Article  CAS  PubMed  Google Scholar 

  70. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247. https://doi.org/10.1126/science.1153124

    Article  CAS  PubMed  Google Scholar 

  71. Grassart A, Cheng AT, Hong SH, Zhang F, Zenzer N, Feng Y, Briner DM, Davis GD, Malkov D, Drubin DG (2014) Actin and dynamin2 dynamics and interplay during clathrin-mediated endocytosis. J Cell Biol 205:721–735. https://doi.org/10.1083/jcb.201403041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wubbolts R, Leckie RS, Veenhuizen PT, Schwarzmann G, Mobius W, Hoernschemeyer J, Slot JW, Geuze HJ, Stoorvogel W (2003) Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. J Biol Chem 278:10963–10972. https://doi.org/10.1074/jbc.M207550200

    Article  CAS  PubMed  Google Scholar 

  73. Sluijter JP, Verhage V, Deddens JC, van den Akker F, Doevendans PA (2014) Microvesicles and exosomes for intracardiac communication. Cardiovasc Res 102:302–311. https://doi.org/10.1093/cvr/cvu022

    Article  CAS  PubMed  Google Scholar 

  74. Barile L, Moccetti T, Marban E, Vassalli G (2017) Roles of exosomes in cardioprotection. Eur Heart J 38:1372–1379. https://doi.org/10.1093/eurheartj/ehw304

    Article  CAS  PubMed  Google Scholar 

  75. Schorey JS, Cheng Y, Singh PP, Smith VL (2015) Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep 16:24–43. https://doi.org/10.15252/embr.201439363

    Article  CAS  PubMed  Google Scholar 

  76. Villarroya-Beltri C, Baixauli F, Gutierrez-Vazquez C, Sanchez-Madrid F, Mittelbrunn M (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28:3–13. https://doi.org/10.1016/j.semcancer.2014.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Obata Y, Kita S, Koyama Y, Fukuda S, Takeda H, Takahashi M, Fujishima Y, Nagao H, Masuda S, Tanaka Y, Nakamura Y, Nishizawa H, Funahashi T, Ranscht B, Izumi Y, Bamba T, Fukusaki E, Hanayama R, Shimada S, Maeda N, Shimomura I (2018) Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release. JCI Insight 3:777. https://doi.org/10.1172/jci.insight.99680

    Article  Google Scholar 

  78. Hyenne V, Labouesse M, Goetz JG (2018) The Small GTPase Ral orchestrates MVB biogenesis and exosome secretion. Small GTPases 9:445–451. https://doi.org/10.1080/21541248.2016.1251378

    Article  CAS  PubMed  Google Scholar 

  79. Crenshaw BJ, Gu L, Sims B, Matthews QL (2018) Exosome biogenesis and biological function in response to viral infections. Open Virol J 12:134–148. https://doi.org/10.2174/1874357901812010134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jones LB, Bell CR, Bibb KE, Gu L, Coats MT, Matthews QL (2018) Pathogens and their effect on exosome biogenesis and composition. Biomedicines 6:777. https://doi.org/10.3390/biomedicines6030079

    Article  CAS  Google Scholar 

  81. Babst M, Katzmann DJ, Snyder WB, Wendland B, Emr SD (2002) Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev Cell 3:283–289

    Article  CAS  PubMed  Google Scholar 

  82. Katzmann DJ, Babst M, Emr SD (2001) Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106:145–155

    Article  CAS  PubMed  Google Scholar 

  83. Hanson PI, Cashikar A (2012) Multivesicular body morphogenesis. Annu Rev Cell Dev Biol 28:337–362. https://doi.org/10.1146/annurev-cellbio-092910-154152

    Article  CAS  PubMed  Google Scholar 

  84. Wollert T, Wunder C, Lippincott-Schwartz J, Hurley JH (2009) Membrane scission by the ESCRT-III complex. Nature 458:172–177. https://doi.org/10.1038/nature07836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Metcalf D, Isaacs AM (2010) The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes. Biochem Soc Trans 38:1469–1473. https://doi.org/10.1042/BST0381469

    Article  CAS  PubMed  Google Scholar 

  86. Kowal J, Tkach M, Thery C (2014) Biogenesis and secretion of exosomes. Curr Opin Cell Biol 29:116–1125. https://doi.org/10.1016/j.ceb.2014.05.004

    Article  CAS  PubMed  Google Scholar 

  87. de Gassart A, Geminard C, Fevrier B, Raposo G, Vidal M (2003) Lipid raft-associated protein sorting in exosomes. Blood 102:4336–4344. https://doi.org/10.1182/blood-2003-03-0871

    Article  CAS  PubMed  Google Scholar 

  88. Roucourt B, Meeussen S, Bao J, Zimmermann P, David G (2015) Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res 25:412–428. https://doi.org/10.1038/cr.2015.29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ghossoub R, Lembo F, Rubio A, Gaillard CB, Bouchet J, Vitale N, Slavik J, Machala M, Zimmermann P (2014) Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat Commun 5:3477. https://doi.org/10.1038/ncomms4477

    Article  CAS  PubMed  Google Scholar 

  90. Henne WM, Buchkovich NJ, Emr SD (2011) The ESCRT pathway. Dev Cell 21:77–91. https://doi.org/10.1016/j.devcel.2011.05.015

    Article  CAS  PubMed  Google Scholar 

  91. Hanson PI, Shim S, Merrill SA (2009) Cell biology of the ESCRT machinery. Curr Opin Cell Biol 21:568–574. https://doi.org/10.1016/j.ceb.2009.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hurley JH (2010) The ESCRT complexes. Crit Rev Biochem Mol Biol 45:463–487. https://doi.org/10.3109/10409238.2010.502516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Raiborg C, Stenmark H (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458:445–452. https://doi.org/10.1038/nature07961

    Article  CAS  PubMed  Google Scholar 

  94. Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S (2001) Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 166:7309–7318. https://doi.org/10.4049/jimmunol.166.12.7309

    Article  CAS  PubMed  Google Scholar 

  95. Mathivanan S, Simpson RJ (2009) ExoCarta: a compendium of exosomal proteins and RNA. Proteomics 9:4997–5000. https://doi.org/10.1002/pmic.200900351

    Article  CAS  PubMed  Google Scholar 

  96. Bowers K, Piper SC, Edeling MA, Gray SR, Owen DJ, Lehner PJ, Luzio JP (2006) Degradation of endocytosed epidermal growth factor and virally ubiquitinated major histocompatibility complex class I is independent of mammalian ESCRTII. J Biol Chem 281:5094–5105. https://doi.org/10.1074/jbc.M508632200

    Article  CAS  PubMed  Google Scholar 

  97. Tamai K, Tanaka N, Nakano T, Kakazu E, Kondo Y, Inoue J, Shiina M, Fukushima K, Hoshino T, Sano K, Ueno Y, Shimosegawa T, Sugamura K (2010) Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem Biophys Res Commun 399:384–390. https://doi.org/10.1016/j.bbrc.2010.07.083

    Article  CAS  PubMed  Google Scholar 

  98. Gross JC, Chaudhary V, Bartscherer K, Boutros M (2012) Active Wnt proteins are secreted on exosomes. Nat Cell Biol 14:1036–1045. https://doi.org/10.1038/ncb2574

    Article  CAS  PubMed  Google Scholar 

  99. Hoshino D, Kirkbride KC, Costello K, Clark ES, Sinha S, Grega-Larson N, Tyska MJ, Weaver AM (2013) Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep 5:1159–1168. https://doi.org/10.1016/j.celrep.2013.10.050

    Article  CAS  PubMed  Google Scholar 

  100. Colombo M, Moita C, van Niel G, Kowal J, Vigneron J, Benaroch P, Manel N, Moita LF, Thery C, Raposo G (2013) Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J Cell Sci 126:5553–5565. https://doi.org/10.1242/jcs.128868

    Article  CAS  PubMed  Google Scholar 

  101. Giordano C, Gelsomino L, Barone I, Panza S, Augimeri G, Bonofiglio D, Rovito D, Naimo GD, Leggio A, Catalano S, Ando S (2019) Leptin modulates exosome biogenesis in breast cancer cells: an additional mechanism in cell-to-cell communication. J Clin Med 8:777. https://doi.org/10.3390/jcm8071027

    Article  CAS  Google Scholar 

  102. Buschow SI, Nolte-'t Hoen EN, van Niel G, Pols MS, ten Broeke T, Lauwen M, Ossendorp F, Melief CJ, Raposo G, Wubbolts R, Wauben MH, Stoorvogel W (2009) MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10:1528–1542. https://doi.org/10.1111/j.1600-0854.2009.00963.x

    Article  CAS  PubMed  Google Scholar 

  103. Abrami L, Brandi L, Moayeri M, Brown MJ, Krantz BA, Leppla SH, van der Goot FG (2013) Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin. Cell Rep 5:986–996. https://doi.org/10.1016/j.celrep.2013.10.019

    Article  CAS  PubMed  Google Scholar 

  104. van Niel G, Wubbolts R, Ten Broeke T, Buschow SI, Ossendorp FA, Melief CJ, Raposo G, van Balkom BW, Stoorvogel W (2006) Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity 25:885–894. https://doi.org/10.1016/j.immuni.2006.11.001

    Article  CAS  PubMed  Google Scholar 

  105. Geminard C, De Gassart A, Blanc L, Vidal M (2004) Degradation of AP2 during reticulocyte maturation enhances binding of hsc70 and Alix to a common site on TFR for sorting into exosomes. Traffic 5:181–193. https://doi.org/10.1111/j.1600-0854.2004.0167.x

    Article  CAS  PubMed  Google Scholar 

  106. Dreux M, Garaigorta U, Boyd B, Decembre E, Chung J, Whitten-Bauer C, Wieland S, Chisari FV (2012) Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. Cell Host Microbe 12:558–570. https://doi.org/10.1016/j.chom.2012.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ (2010) Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol 190:1079–1091. https://doi.org/10.1083/jcb.201002049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452. https://doi.org/10.1074/jbc.M110.107821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Verweij FJ, van Eijndhoven MA, Hopmans ES, Vendrig T, Wurdinger T, Cahir-McFarland E, Kieff E, Geerts D, van der Kant R, Neefjes J, Middeldorp JM, Pegtel DM (2011) LMP1 association with CD63 in endosomes and secretion via exosomes limits constitutive NF-kappaB activation. EMBO J 30:2115–2129. https://doi.org/10.1038/emboj.2011.123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. van Niel G, Charrin S, Simoes S, Romao M, Rochin L, Saftig P, Marks MS, Rubinstein E, Raposo G (2011) The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell 21:708–721. https://doi.org/10.1016/j.devcel.2011.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, Lochnit G, Preissner KT, Zoller M (2010) Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 70:1668–1678. https://doi.org/10.1158/0008-5472.CAN-09-2470

    Article  CAS  PubMed  Google Scholar 

  112. Perez-Hernandez D, Gutierrez-Vazquez C, Jorge I, Lopez-Martin S, Ursa A, Sanchez-Madrid F, Vazquez J, Yanez-Mo M (2013) The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem 288:11649–11661. https://doi.org/10.1074/jbc.M112.445304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhu H, Guariglia S, Yu RY, Li W, Brancho D, Peinado H, Lyden D, Salzer J, Bennett C, Chow CW (2013) Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol Biol Cell 24(1619–37):S1–3. https://doi.org/10.1091/mbc.E12-07-0544

    Article  CAS  Google Scholar 

  114. Ponnambalam S, Baldwin SA (2003) Constitutive protein secretion from the trans-Golgi network to the plasma membrane. Mol Membr Biol 20:129–139. https://doi.org/10.1080/0968768031000084172

    Article  CAS  PubMed  Google Scholar 

  115. Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Gronborg M, Mobius W, Rhee J, Barr FA, Simons M (2010) Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol 189:223–232. https://doi.org/10.1083/jcb.200911018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284:34211–34222. https://doi.org/10.1074/jbc.M109.041152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yu X, Harris SL, Levine AJ (2006) The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res 66:4795–4801. https://doi.org/10.1158/0008-5472.CAN-05-4579

    Article  CAS  PubMed  Google Scholar 

  118. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine JC, Vidal M, Amson R, Telerman A (2008) Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death Differ 15:1723–1733. https://doi.org/10.1038/cdd.2008.104

    Article  CAS  PubMed  Google Scholar 

  119. Qu Y, Dubyak GR (2009) P2X7 receptors regulate multiple types of membrane trafficking responses and non-classical secretion pathways. Purinergic Signal 5:163–173. https://doi.org/10.1007/s11302-009-9132-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Savina A, Furlan M, Vidal M, Colombo MI (2003) Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem 278:20083–20090. https://doi.org/10.1074/jbc.M301642200

    Article  CAS  PubMed  Google Scholar 

  121. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851. https://doi.org/10.1523/JNEUROSCI.5699-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gupta S, Knowlton AA (2007) HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am J Physiol Heart Circ Physiol 292:H3052–H3056. https://doi.org/10.1152/ajpheart.01355.2006

    Article  CAS  PubMed  Google Scholar 

  124. Genneback N, Hellman U, Malm L, Larsson G, Ronquist G, Waldenstrom A, Morner S (2013) Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes. J Extracell Vesicles. https://doi.org/10.3402/jev.v2i0.20167

    Article  PubMed  PubMed Central  Google Scholar 

  125. Malik ZA, Kott KS, Poe AJ, Kuo T, Chen L, Ferrara KW, Knowlton AA (2013) Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am J Physiol Heart Circ Physiol 304:H954–H965. https://doi.org/10.1152/ajpheart.00835.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Amzallag N, Passer BJ, Allanic D, Segura E, Thery C, Goud B, Amson R, Telerman A (2004) TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. J Biol Chem 279:46104–46112. https://doi.org/10.1074/jbc.M404850200

    Article  CAS  PubMed  Google Scholar 

  127. Cai H, Reinisch K, Ferro-Novick S (2007) Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev Cell 12:671–682. https://doi.org/10.1016/j.devcel.2007.04.005

    Article  CAS  PubMed  Google Scholar 

  128. Sonnichsen B, De Renzis S, Nielsen E, Rietdorf J, Zerial M (2000) Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J Cell Biol 149:901–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Savina A, Vidal M, Colombo MI (2002) The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci 115:2505–2515

    CAS  PubMed  Google Scholar 

  130. Sinha S, Hoshino D, Hong NH, Kirkbride KC, Grega-Larson NE, Seiki M, Tyska MJ, Weaver AM (2016) Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol 214:197–213. https://doi.org/10.1083/jcb.201601025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Koles K, Nunnari J, Korkut C, Barria R, Brewer C, Li Y, Leszyk J, Zhang B, Budnik V (2012) Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons. J Biol Chem 287:16820–16834. https://doi.org/10.1074/jbc.M112.342667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Savina A, Fader CM, Damiani MT, Colombo MI (2005) Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 6:131–143. https://doi.org/10.1111/j.1600-0854.2004.00257.x

    Article  CAS  PubMed  Google Scholar 

  133. Heijnen HF, Debili N, Vainchencker W, Breton-Gorius J, Geuze HJ, Sixma JJ (1998) Multivesicular bodies are an intermediate stage in the formation of platelet alpha-granules. Blood 91:2313–2325

    Article  CAS  PubMed  Google Scholar 

  134. Wilson HL, Francis SE, Dower SK, Crossman DC (2004) Secretion of intracellular IL-1 receptor antagonist (type 1) is dependent on P2X7 receptor activation. J Immunol 173:1202–1208. https://doi.org/10.4049/jimmunol.173.2.1202

    Article  CAS  PubMed  Google Scholar 

  135. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G, Hivroz C (2002) TCR Activation of human T cells induces the production of exosomes bearing the TCR/CD3/ complex. J Immunol 168:3235–3241. https://doi.org/10.4049/jimmunol.168.7.3235

    Article  CAS  PubMed  Google Scholar 

  136. Pfeffer SR (2007) Unsolved mysteries in membrane traffic. Annu Rev Biochem 76:629–645. https://doi.org/10.1146/annurev.biochem.76.061705.130002

    Article  CAS  PubMed  Google Scholar 

  137. Bonifacino JS, Glick BS (2004) The mechanisms of vesicle budding and fusion. Cell 116:153–166

    Article  CAS  PubMed  Google Scholar 

  138. Rao SK, Huynh C, Proux-Gillardeaux V, Galli T, Andrews NW (2004) Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis. J Biol Chem 279:20471–20479. https://doi.org/10.1074/jbc.M400798200

    Article  CAS  PubMed  Google Scholar 

  139. Tiwari N, Wang CC, Brochetta C, Ke G, Vita F, Qi Z, Rivera J, Soranzo MR, Zabucchi G, Hong W, Blank U (2008) VAMP-8 segregates mast cell-preformed mediator exocytosis from cytokine trafficking pathways. Blood 111:3665–3674. https://doi.org/10.1182/blood-2007-07-103309

    Article  CAS  PubMed  Google Scholar 

  140. Puri N, Roche PA (2008) Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms. Proc Natl Acad Sci USA 105:2580–2585. https://doi.org/10.1073/pnas.0707854105

    Article  PubMed  PubMed Central  Google Scholar 

  141. Logan MR, Lacy P, Odemuyiwa SO, Steward M, Davoine F, Kita H, Moqbel R (2006) A critical role for vesicle-associated membrane protein-7 in exocytosis from human eosinophils and neutrophils. Allergy 61:777–784. https://doi.org/10.1111/j.1398-9995.2006.01089.x

    Article  CAS  PubMed  Google Scholar 

  142. Antonin W, Fasshauer D, Becker S, Jahn R, Schneider TR (2002) Crystal structure of the endosomal SNARE complex reveals common structural principles of all SNAREs. Nat Struct Biol 9:107–111. https://doi.org/10.1038/nsb746

    Article  CAS  PubMed  Google Scholar 

  143. Rossi V, Banfield DK, Vacca M, Dietrich LE, Ungermann C, D'Esposito M, Galli T, Filippini F (2004) Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators. Trends Biochem Sci 29:682–688. https://doi.org/10.1016/j.tibs.2004.10.002

    Article  CAS  PubMed  Google Scholar 

  144. Advani RJ, Yang B, Prekeris R, Lee KC, Klumperman J, Scheller RH (1999) VAMP-7 mediates vesicular transport from endosomes to lysosomes. J Cell Biol 146:765–776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Fader CM, Sanchez DG, Mestre MB, Colombo MI (2009) TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim Biophys Acta 1793:1901–1916. https://doi.org/10.1016/j.bbamcr.2009.09.011

    Article  CAS  PubMed  Google Scholar 

  146. Ruiz-Martinez M, Navarro A, Marrades RM, Vinolas N, Santasusagna S, Munoz C, Ramirez J, Molins L, Monzo M (2016) YKT6 expression, exosome release, and survival in non-small cell lung cancer. Oncotarget 7:51515–51524. https://doi.org/10.18632/oncotarget.9862

    Article  PubMed  PubMed Central  Google Scholar 

  147. Simons M, Raposo G (2009) Exosomes—vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581. https://doi.org/10.1016/j.ceb.2009.03.007

    Article  CAS  PubMed  Google Scholar 

  148. Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ (2010) Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 9:197–208. https://doi.org/10.1074/mcp.M900152-MCP200

    Article  CAS  PubMed  Google Scholar 

  149. Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ, Chang LF, Zhou Q, Sui SF (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11:675–687. https://doi.org/10.1111/j.1600-0854.2010.01041.x

    Article  CAS  PubMed  Google Scholar 

  150. Doherty GJ, McMahon HT (2009) Mechanisms of endocytosis. Annu Rev Biochem 78:857–902. https://doi.org/10.1146/annurev.biochem.78.081307.110540

    Article  CAS  PubMed  Google Scholar 

  151. Swanson JA (2008) Shaping cups into phagosomes and macropinosomes. Nat Rev Mol Cell Biol 9:639–649. https://doi.org/10.1038/nrm2447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rudt S, Müller RH (1993) In vitro phagocytosis assay of nano- and microparticles by chemiluminescence. III. Uptake of differently sized surface-modified particles, and its correlation to particle properties and in vivo distribution. Eur J Pharm Sci 1:31–39. https://doi.org/10.1016/0928-0987(93)90015-3

    Article  Google Scholar 

  153. Wu Y, Wu W, Wong WM, Ward E, Thrasher AJ, Goldblatt D, Osman M, Digard P, Canaday DH, Gustafsson K (2009) Human gamma delta T cells: a lymphoid lineage cell capable of professional phagocytosis. J Immunol 183:5622–5629. https://doi.org/10.4049/jimmunol.0901772

    Article  CAS  PubMed  Google Scholar 

  154. Shiratsuchi A, Kaido M, Takizawa T, Nakanishi Y (2000) Phosphatidylserine-mediated phagocytosis of influenza A virus-infected cells by mouse peritoneal macrophages. J Virol 74:9240–9244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439. https://doi.org/10.1038/nature06307

    Article  CAS  PubMed  Google Scholar 

  156. Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD Jr, Thomson AW (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257–3266. https://doi.org/10.1182/blood-2004-03-0824

    Article  CAS  PubMed  Google Scholar 

  157. Gold ES, Underhill DM, Morrissette NS, Guo J, McNiven MA, Aderem A (1999) Dynamin 2 is required for phagocytosis in macrophages. J Exp Med 190:1849–1856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Stephens L, Ellson C, Hawkins P (2002) Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 14:203–213. https://doi.org/10.1016/s0955-0674(02)00311-3

    Article  CAS  PubMed  Google Scholar 

  159. Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, Eskelinen EL (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117:4837–4848. https://doi.org/10.1242/jcs.01370

    Article  CAS  PubMed  Google Scholar 

  160. Kerr MC, Teasdale RD (2009) Defining macropinocytosis. Traffic 10:364–371. https://doi.org/10.1111/j.1600-0854.2009.00878.x

    Article  CAS  PubMed  Google Scholar 

  161. Grimmer S, van Deurs B, Sandvig K (2002) Membrane ruffling and macropinocytosis in A431 cells require cholesterol. J Cell Sci 115:2953–2962

    CAS  PubMed  Google Scholar 

  162. Ahram M, Sameni M, Qiu RG, Linebaugh B, Kirn D, Sloane BF (2000) Rac1-induced endocytosis is associated with intracellular proteolysis during migration through a three-dimensional matrix. Exp Cell Res 260:292–303. https://doi.org/10.1006/excr.2000.5031

    Article  CAS  PubMed  Google Scholar 

  163. Gao YS, Hubbert CC, Lu J, Lee YS, Lee JY, Yao TP (2007) Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis. Mol Cell Biol 27:8637–8647. https://doi.org/10.1128/MCB.00393-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Amyere M, Payrastre B, Krause U, Van Der Smissen P, Veithen A, Courtoy PJ (2000) Constitutive macropinocytosis in oncogene-transformed fibroblasts depends on sequential permanent activation of phosphoinositide 3-kinase and phospholipase C. Mol Biol Cell 11:3453–3467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Veithen A, Cupers P, Baudhuin P, Courtoy PJ (1996) v-Src induces constitutive macropinocytosis in rat fibroblasts. J Cell Sci 109(Pt 8):2005–2012

    CAS  PubMed  Google Scholar 

  166. Tian T, Zhu YL, Zhou YY, Liang GF, Wang YY, Hu FH, Xiao ZD (2014) Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J Biol Chem 289:22258–22267. https://doi.org/10.1074/jbc.M114.588046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 124:447–458. https://doi.org/10.1242/jcs.074088

    Article  CAS  PubMed  Google Scholar 

  168. Mercer J, Helenius A (2008) Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 320:531–535. https://doi.org/10.1126/science.1155164

    Article  CAS  PubMed  Google Scholar 

  169. Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci USA 110:17380–17385. https://doi.org/10.1073/pnas.1304266110

    Article  PubMed  PubMed Central  Google Scholar 

  170. Nanbo A, Kawanishi E, Yoshida R, Yoshiyama H (2013) Exosomes derived from Epstein-Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J Virol 87:10334–10347. https://doi.org/10.1128/JVI.01310-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Kirchhausen T (2000) Clathrin. Annu Rev Biochem 69:699–727. https://doi.org/10.1146/annurev.biochem.69.1.699

    Article  CAS  PubMed  Google Scholar 

  172. Wang LH, Rothberg KG, Anderson RG (1993) Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol 123:1107–1117

    Article  CAS  PubMed  Google Scholar 

  173. Escrevente C, Keller S, Altevogt P, Costa J (2011) Interaction and uptake of exosomes by ovarian cancer cells. BMC Cancer 11:108. https://doi.org/10.1186/1471-2407-11-108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Traub LM (2003) Sorting it out: AP-2 and alternate clathrin adaptors in endocytic cargo selection. J Cell Biol 163:203–208. https://doi.org/10.1083/jcb.200309175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kirchhausen T, Bonifacino JS, Riezman H (1997) Linking cargo to vesicle formation: receptor tail interactions with coat proteins. Curr Opin Cell Biol 9:488–495

    Article  CAS  PubMed  Google Scholar 

  176. Robinson MS (2004) Adaptable adaptors for coated vesicles. Trends Cell Biol 14:167–174. https://doi.org/10.1016/j.tcb.2004.02.002

    Article  CAS  PubMed  Google Scholar 

  177. Benmerah A, Bayrou M, Cerf-Bensussan N, Dautry-Varsat A (1999) Inhibition of clathrin-coated pit assembly by an Eps15 mutant. J Cell Sci 112(Pt 9):1303–1311

    CAS  PubMed  Google Scholar 

  178. Ehrlich M, Boll W, Van Oijen A, Hariharan R, Chandran K, Nibert ML, Kirchhausen T (2004) Endocytosis by random initiation and stabilization of clathrin-coated pits. Cell 118:591–605. https://doi.org/10.1016/j.cell.2004.08.017

    Article  CAS  PubMed  Google Scholar 

  179. Merrifield CJ, Feldman ME, Wan L, Almers W (2002) Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits. Nat Cell Biol 4:691–698. https://doi.org/10.1038/ncb837

    Article  CAS  PubMed  Google Scholar 

  180. Taylor MJ, Lampe M, Merrifield CJ (2012) A feedback loop between dynamin and actin recruitment during clathrin-mediated endocytosis. PLoS Biol 10:e1001302. https://doi.org/10.1371/journal.pbio.1001302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Barres C, Blanc L, Bette-Bobillo P, Andre S, Mamoun R, Gabius HJ, Vidal M (2010) Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 115:696–705. https://doi.org/10.1182/blood-2009-07-231449

    Article  CAS  PubMed  Google Scholar 

  182. Anderson RG (1998) The caveolae membrane system. Annu Rev Biochem 67:199–225. https://doi.org/10.1146/annurev.biochem.67.1.199

    Article  CAS  PubMed  Google Scholar 

  183. Nabi IR, Le PU (2003) Caveolae/raft-dependent endocytosis. J Cell Biol 161:673–677. https://doi.org/10.1083/jcb.200302028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Kurzchalia TV, Partan RG (1999) Membrane microdomains and caveolae. Curr Opin Cell Biol 11:424–431. https://doi.org/10.1016/S0955-0674(99)80061-1

    Article  CAS  PubMed  Google Scholar 

  185. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452. https://doi.org/10.1126/science.1062688

    Article  CAS  PubMed  Google Scholar 

  186. Razani B, Woodman SE, Lisanti MP (2002) Caveolae: from cell biology to animal physiology. Pharmacol Rev 54:431–467

    Article  CAS  PubMed  Google Scholar 

  187. Svensson KJ, Christianson HC, Wittrup A, Bourseau-Guilmain E, Lindqvist E, Svensson LM, Morgelin M, Belting M (2013) Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J Biol Chem 288:17713–17724. https://doi.org/10.1074/jbc.M112.445403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194. https://doi.org/10.1038/nrm2122

    Article  CAS  PubMed  Google Scholar 

  189. Menck K, Klemm F, Gross JC, Pukrop T, Wenzel D, Binder C (2013) Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles. Oncotarget 4:2057–2066. https://doi.org/10.18632/oncotarget.1336

    Article  PubMed  PubMed Central  Google Scholar 

  190. Orth JD, Krueger EW, Cao H, McNiven MA (2002) The large GTPase dynamin regulates actin comet formation and movement in living cells. Proc Natl Acad Sci USA 99:167–172. https://doi.org/10.1073/pnas.012607899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Chernomordik LV, Kozlov MM (2008) Mechanics of membrane fusion. Nat Struct Mol Biol 15:675–683. https://doi.org/10.1038/nsmb.1455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Jahn R, Lang T, Sudhof TC (2003) Membrane fusion. Cell 112:519–533

    Article  CAS  PubMed  Google Scholar 

  193. Chernomordik LV, Melikyan GB, Chizmadzhev YA (1987) Biomembrane fusion: a new concept derived from model studies using two interacting planar lipid bilayers. Biochim Biophys Acta 906:309–352

    Article  CAS  PubMed  Google Scholar 

  194. Jahn R, Sudhof TC (1999) Membrane fusion and exocytosis. Annu Rev Biochem 68:863–911. https://doi.org/10.1146/annurev.biochem.68.1.863

    Article  CAS  PubMed  Google Scholar 

  195. Del Conde I, Shrimpton CN, Thiagarajan P, Lopez JA (2005) Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood 106:1604–1611. https://doi.org/10.1182/blood-2004-03-1095

    Article  CAS  PubMed  Google Scholar 

  196. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z, Milosevic J, Tkacheva OA, Divito SJ, Jordan R, Lyons-Weiler J, Watkins SC, Morelli AE (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766. https://doi.org/10.1182/blood-2011-02-338004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work received support from Natural Sciences and Engineering Research Council of Canada (NSERC; Operating grant to V.B.P.), Canadian Institutes of Health Research (CIHR; Operating grant to V.B.P.), and Libin Cardiovascular Institute of Alberta, Cumming School of Medicine (Start-up operating Fund to V.B.P.; Postdoctoral scholarship to A.S.J.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Vaibhav B. Patel.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jadli, A.S., Ballasy, N., Edalat, P. et al. Inside(sight) of tiny communicator: exosome biogenesis, secretion, and uptake. Mol Cell Biochem 467, 77–94 (2020). https://doi.org/10.1007/s11010-020-03703-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-03703-z

Keywords

Navigation