Exosomes: from biogenesis and secretion to biological function.

Exosomes are small microvesicles that are released from late endosomal compartments of cultured cells. Recent work has shown that exosome-like vesicles are also found in many body fluids such as blood, urine, ascites and amnionic fluid. Although the biological function of exosomes is far from being fully understood, exosomes may have general importance in cell biology and immunology. The present review aims to address some of the facets of exosome research with particular emphasis on the immunologist's perspective: (i) exosomes as a novel platform for the ectodomain shedding of membrane proteins by ADAMs and (ii) recent findings on the role of exosomes in tumor biology and immune regulation.

[1]  G. Raposo,et al.  Lipid raft-associated protein sorting in exosomes. , 2003, Blood.

[2]  Peter A Lawrence,et al.  Morphogens, Compartments, and Pattern: Lessons from Drosophila? , 1996, Cell.

[3]  Alzheimer's disease beta-amyloid peptides are released in association with exosomes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Chin,et al.  Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis , 2005 .

[5]  H. Geuze,et al.  Selective Enrichment of Tetraspan Proteins on the Internal Vesicles of Multivesicular Endosomes and on Exosomes Secreted by Human B-lymphocytes* , 1998, The Journal of Biological Chemistry.

[6]  A. Ullrich,et al.  Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body , 1990, Cell.

[7]  C. Futter,et al.  Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes , 1996, The Journal of cell biology.

[8]  E. Rovida,et al.  Transmodulation of Cell Surface Regulatory Molecules via Ectodomain Shedding , 2002, Biological chemistry.

[9]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[10]  P. Selby,et al.  Proteomic analysis of melanoma‐derived exosomes by two‐dimensional polyacrylamide gel electrophoresis and mass spectrometry , 2004, Proteomics.

[11]  S. Cohen,et al.  Problems and paradigms: Morphogens and pattern formation , 1997 .

[12]  A. Namane,et al.  Mast Cell-Dependent B and T Lymphocyte Activation Is Mediated by the Secretion of Immunologically Active Exosomes1 , 2001, The Journal of Immunology.

[13]  Bart N Lambrecht,et al.  Proteomic analysis of exosomes isolated from human malignant pleural effusions. , 2004, American journal of respiratory cell and molecular biology.

[14]  S. Eaton,et al.  Argosomes A Potential Vehicle for the Spread of Morphogens through Epithelia , 2001, Cell.

[15]  W. Sundquist,et al.  The Protein Network of HIV Budding , 2003, Cell.

[16]  R. Johnstone,et al.  Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions. , 1989, Blood.

[17]  P. Altevogt,et al.  A role for exosomes in the constitutive and stimulus-induced ectodomain cleavage of L1 and CD44. , 2006, The Biochemical journal.

[18]  P. P. Di Fiore,et al.  Endocytosis and mitogenic signaling. , 1999, Current opinion in cell biology.

[19]  J. Christian,et al.  BMP, Wnt and Hedgehog signals: how far can they go? , 2000, Current opinion in cell biology.

[20]  G. Lachenal,et al.  Exosomes are released by cultured cortical neurones , 2006, Molecular and Cellular Neuroscience.

[21]  L. Zitvogel,et al.  Prospects for exosomes in immunotherapy of cancer , 2006, Journal of cellular and molecular medicine.

[22]  H. Schluesener,et al.  Role of exosomes in immune regulation , 2006, Journal of cellular and molecular medicine.

[23]  D. Skokos,et al.  Immunoregulatory properties of mast cell-derived exosomes. , 2002, Molecular immunology.

[24]  司 竹村,et al.  細胞接着における膜結合型Heparin-binding EGF-like growth factorの生物学的機能 , 2008 .

[25]  Laurence Zitvogel,et al.  Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming , 2001, Nature Medicine.

[26]  S Cohen,et al.  Morphogens and pattern formation. , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[27]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[28]  A. Rudensky,et al.  Reorganization of multivesicular bodies regulates MHC class II antigen presentation by dendritic cells , 2001, The Journal of cell biology.

[29]  M. Kaler,et al.  Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. Novikoff,et al.  GOLGI APPARATUS AND LYSOSOMES. , 1964, Federation proceedings.

[31]  G. Raposo,et al.  Intestinal epithelial cells secrete exosome-like vesicles. , 2001, Gastroenterology.

[32]  R. D. Fisher,et al.  Structure and Ubiquitin Binding of the Ubiquitin-interacting Motif* , 2003, Journal of Biological Chemistry.

[33]  S. Emr,et al.  Fab1p PtdIns(3)P 5-Kinase Function Essential for Protein Sorting in the Multivesicular Body , 1998, Cell.

[34]  P. Ricciardi-Castagnoli,et al.  Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles1 , 2001, The Journal of Immunology.

[35]  A. Régnault,et al.  TCR Activation of Human T Cells Induces the Production of Exosomes Bearing the TCR/CD3/ζ Complex1 , 2002, The Journal of Immunology.

[36]  William E. Grizzle,et al.  Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function1 , 2006, The Journal of Immunology.

[37]  A. Namane,et al.  Nonspecific B and T Cell-Stimulatory Activity Mediated by Mast CellsIs Associated with Exosomes , 2001, International Archives of Allergy and Immunology.

[38]  L. Zitvogel,et al.  The potential of exosomes in immunotherapy , 2005, Expert opinion on biological therapy.

[39]  S. Schmid,et al.  Regulation of signal transduction by endocytosis. , 2000, Current opinion in cell biology.

[40]  M. Mason,et al.  Induction of heat shock proteins in B-cell exosomes , 2005, Journal of Cell Science.

[41]  P. Altevogt,et al.  Cleavage of L1 in Exosomes and Apoptotic Membrane Vesicles Released from Ovarian Carcinoma Cells , 2005, Clinical Cancer Research.

[42]  Rong-Fong Shen,et al.  Identification and proteomic profiling of exosomes in human urine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[43]  S. Amigorena,et al.  Anti-tumour immunotherapy using dendritic-cell-derived exosomes. , 1998, Research in immunology.

[44]  K. Shedden,et al.  Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. , 2003, Cancer research.

[45]  M. Klagsbrun,et al.  Heparin-binding Epidermal Growth Factor-like Growth Factor (HB-EGF) is a Mediator of Multiple Physiological and Pathological Pathways , 2004, Growth factors.

[46]  H. Geuze,et al.  Late endosomes derive from early endosomes by maturation , 1991, Cell.

[47]  Masafumi Nakamura,et al.  Purification, characterization and biological significance of tumor-derived exosomes. , 2005, Anticancer research.

[48]  J. Sprent,et al.  Direct stimulation of T cells by membrane vesicles from antigen-presenting cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  P. Altevogt,et al.  ADAM10‐mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  L. Zitvogel,et al.  Dendritic cell-based immunotherapy of cancer. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[51]  C. Melief,et al.  Antigen Loading of MHC Class I Molecules in the Endocytic Tract , 2001, Traffic.

[52]  Veronica Huber,et al.  Induction of Lymphocyte Apoptosis by Tumor Cell Secretion of FasL-bearing Microvesicles , 2002, The Journal of experimental medicine.

[53]  J. Luzio,et al.  Fusion of Lysosomes with Late Endosomes Produces a Hybrid Organelle of Intermediate Density and Is NSF Dependent , 1998, The Journal of cell biology.

[54]  J. Slot,et al.  Proteomic and Biochemical Analyses of Human B Cell-derived Exosomes , 2003, The Journal of Biological Chemistry.

[55]  G. Raposo,et al.  Prions and exosomes: from PrPc trafficking to PrPsc propagation. , 2005, Blood cells, molecules & diseases.

[56]  Skokos Dimitris,et al.  Immunoregulatory properties of mast cell-derived exosomes. , 2002 .

[57]  W. Faigle,et al.  Cells release prions in association with exosomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[58]  R. Johnstone,et al.  Exosomes biological significance: A concise review. , 2006, Blood cells, molecules & diseases.

[59]  I. Mellman Membranes and sorting. , 1996, Current opinion in cell biology.

[60]  P. Dempsey,et al.  Control of ErbB signaling through metalloprotease mediated ectodomain shedding of EGF-like factors , 2006, Growth factors.

[61]  E. Schwoebel,et al.  The control of gene expression by regulated nuclear transport. , 2000, Essays in biochemistry.

[62]  Laurence Zitvogel,et al.  Exosomes: composition, biogenesis and function , 2002, Nature Reviews Immunology.

[63]  P. P. D. Fiore,et al.  Endocytosis and mitogenic signaling. , 1999 .

[64]  I. Mellman Endocytosis and molecular sorting. , 1996, Annual review of cell and developmental biology.

[65]  J J Sixma,et al.  Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. , 1999, Blood.

[66]  K. Cadigan Regulating morphogen gradients in the Drosophila wing. , 2002, Seminars in cell & developmental biology.

[67]  M. Freeman,et al.  BAG-1 Is a Novel Cytoplasmic Binding Partner of the Membrane Form of Heparin-binding EGF-like Growth Factor , 2001, The Journal of Biological Chemistry.

[68]  Sibel Akyol,et al.  Pregnancy-Associated Exosomes and Their Modulation of T Cell Signaling1 , 2006, The Journal of Immunology.

[69]  A. Levine,et al.  The regulation of exosome secretion: a novel function of the p53 protein. , 2006, Cancer research.

[70]  T. Ichim,et al.  Tumor exosomes expressing fas ligand mediate CD8+ T cell apoptosis , 2004, Annals of Surgical Oncology.

[71]  Michael A. Gibson,et al.  Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells , 2005, Molecular Cancer Therapeutics.

[72]  S. Meri,et al.  Complement inhibitor membrane cofactor protein (MCP; CD46) is constitutively shed from cancer cell membranes in vesicles and converted by a metalloproteinase to a functionally active soluble form , 2004, European journal of immunology.