The Biogenesis and Functions of Exosomes

Exosomes are membrane vesicles with a diameter of 40–100 nm that are secreted by many cell types into the extracellular milieu. They correspond to the internal vesicles of an endosomal compartment, the multivesicular body and are released upon exocytic fusion of this organelle with the plasma membrane. Intracellularly, they are formed by inward budding of the endosomal membrane in a process that sequesters particular proteins and lipids. The unique composition of exosomes may confer specific functions on them upon secretion. Although their physiological role in vivo is far from being unraveled, it is apparent that they function in a multitude of processes, including intercellular communication during the immune response. Exosomes may have evolved early in the evolution of multicellular organisms and also seem to be important for tissue developmental processes.

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

[2]  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.

[3]  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.

[4]  M. Vidal,et al.  Exosomes released during reticulocyte maturation bind to fibronectin via integrin alpha4beta1. , 2000, European journal of biochemistry.

[5]  J. Mills AIDS and AIDS-related infections: Current strategies for Prevention and therapy: edited by Adrian Bint and John Oxford, Academic Press, 1989. £12.50 (v + 137 pages) ISBN 12 099200 0 , 1990 .

[6]  S. Emr,et al.  Ubiquitin-Dependent Sorting into the Multivesicular Body Pathway Requires the Function of a Conserved Endosomal Protein Sorting Complex, ESCRT-I , 2001, Cell.

[7]  A. Thomson,et al.  Designer dendritic cells for tolerance induction: guided not misguided missiles. , 2001, Trends in immunology.

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

[9]  S. Pentyala,et al.  Prostasomes: Current concepts , 2000, The Prostate.

[10]  A. Pelchen-Matthews,et al.  Endocytosis in Viral Replication , 2000, Traffic.

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

[12]  M. Hemler,et al.  Role of Transmembrane 4 Superfamily (Tm4sf) Proteins Cd9 and Cd81 in Muscle Cell Fusion and Myotube Maintenance , 1999, The Journal of cell biology.

[13]  M. Vidal,et al.  Decay-accelerating factor (CD55) and membrane inhibitor of reactive lysis (CD59) are released within exosomes during In vitro maturation of reticulocytes. , 1998, Blood.

[14]  T. Schwartz,et al.  The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. , 2001, Molecular biology of the cell.

[15]  M. Vidal,et al.  Exosomes released during reticulocyte maturation bind to fibronectin via integrin α4β1 , 2000 .

[16]  R. Palmiter,et al.  Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport , 1999, Nature Cell Biology.

[17]  Laurence Zitvogel,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

[18]  W. Huttner,et al.  Implications of lipid microdomains for membrane curvature, budding and fission. , 2001, Current opinion in cell biology.

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

[20]  L. Traub,et al.  Sorting in the endosomal system in yeast and animal cells. , 2000, Current opinion in cell biology.

[21]  J. Cochran,et al.  Receptor clustering and transmembrane signaling in T cells. , 2001, Trends in biochemical sciences.

[22]  H. Geuze The role of endosomes and lysosomes in MHC class II functioning. , 1998, Immunology today.

[23]  S. Pals,et al.  Triple check for antigen specificity of B cells during germinal centre reactions. , 1997, Immunology today.

[24]  J. Neefjes,et al.  Direct vesicular transport of MHC class II molecules from lysosomal structures to the cell surface , 1996, The Journal of cell biology.

[25]  J. Slot,et al.  Immunoelectron Microscopic Localization of Cholesterol Using Biotinylated and Non-cytolytic Perfringolysin O , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[26]  G. Raposo,et al.  Accumulation of Major Histocompatibility Complex Class Ii Molecules in Mast Cell Secretory Granules and Their Release upon Degranulation Generation of Bmmcs Preparation of B Cells Reagents and Monoclonal Antibodies (mabs) Immunofluorescence Staining and Confocal Microscopy Pulse-chase# Labeling and , 2022 .

[27]  R Keller,et al.  Dendritic cells: their significance in health and disease. , 2001, Immunology letters.

[28]  M. Mann,et al.  The Exosome: A Conserved Eukaryotic RNA Processing Complex Containing Multiple 3′→5′ Exoribonucleases , 1997, Cell.

[29]  E. Ikonen,et al.  Roles of lipid rafts in membrane transport. , 2001, Current opinion in cell biology.

[30]  B. Pan,et al.  Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor , 1983, Cell.

[31]  C. Boucheix,et al.  CD9, CD63, CD81, and CD82 are components of a surface tetraspan network connected to HLA‐DR and VLA integrins , 1996, European journal of immunology.

[32]  J. Klumperman,et al.  Bilayered clathrin coats on endosomal vacuoles are involved in protein sorting toward lysosomes. , 2002, Molecular biology of the cell.

[33]  R. Johnstone,et al.  Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). , 1987, The Journal of biological chemistry.

[34]  H. Geuze,et al.  Segregation of MHC class II molecules from MHC class I molecules in the Golgi complex for transport to lysosomal compartments , 1991, Nature.

[35]  P. Cresswell,et al.  The tetraspan protein CD82 is a resident of MHC class II compartments where it associates with HLA-DR, -DM, and -DO molecules. , 1998, Journal of immunology.

[36]  I. Hilgert,et al.  Association of four antigens of the tetraspans family (CD37, CD53, TAPA-1, and R2/C33) with MHC class II glycoproteins , 2004, Immunogenetics.

[37]  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.

[38]  M. Vidal,et al.  Aggregation reroutes molecules from a recycling to a vesicle-mediated secretion pathway during reticulocyte maturation. , 1997, Journal of cell science.

[39]  Sushmita Mukherjee,et al.  Endocytic Sorting of Lipid Analogues Differing Solely in the Chemistry of Their Hydrophobic Tails , 1999, The Journal of cell biology.

[40]  M. Vidal,et al.  Characteristics of the Interaction between Hsc70 and the Transferrin Receptor in Exosomes Released during Reticulocyte Maturation* , 2001, The Journal of Biological Chemistry.

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

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

[43]  M. Edidin,et al.  Shrinking patches and slippery rafts: scales of domains in the plasma membrane. , 2001, Trends in cell biology.

[44]  M. Gonzalez-Gaitan,et al.  Morphogen Gradient Formation and Vesicular Trafficking , 2002, Traffic.

[45]  O. Yoshie,et al.  Molecular analyses of the association of CD4 with two members of the transmembrane 4 superfamily, CD81 and CD82. , 1995, Journal of immunology.

[46]  H. Langen,et al.  Tetraspan microdomains distinct from lipid rafts enrich select peptide–MHC class II complexes , 2002, Nature Immunology.

[47]  Masashi Yamada,et al.  Maternal Pumilio acts together with Nanos in germline development in Drosophila embryos , 1999, Nature Cell Biology.

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

[49]  P. Peters,et al.  A new model for lethal hit delivery by cytotoxic T lymphocytes. , 1990, Immunology today.

[50]  M. Karlsson,et al.  "Tolerosomes" are produced by intestinal epithelial cells , 2001, European journal of immunology.

[51]  P. Webster,et al.  Lysosomes Behave as Ca2+-regulated Exocytic Vesicles in Fibroblasts and Epithelial Cells , 1997, The Journal of cell biology.

[52]  D. Gray,et al.  Novel pathways of antigen presentation for the maintenance of memory. , 1991, International immunology.

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

[54]  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.

[55]  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.

[56]  A. Enk,et al.  Dendritic cells as a tool to induce anergic and regulatory T cells. , 2001, Trends in immunology.

[57]  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.

[58]  G. Dveksler,et al.  Murine CD9 Is the Receptor for Pregnancy-specific Glycoprotein 17 , 2002, The Journal of experimental medicine.

[59]  Xiaolong Wei,et al.  Hrs Interacts with Sorting Nexin 1 and Regulates Degradation of Epidermal Growth Factor Receptor* , 2001, The Journal of Biological Chemistry.

[60]  S. Davanger,et al.  Hrs-2 Regulates Receptor-mediated Endocytosis via Interactions with Eps15* , 2000, The Journal of Biological Chemistry.

[61]  B. Deurs,et al.  Multivesicular bodies in HEp-2 cells are maturing endosomes. , 1993, European journal of cell biology.

[62]  K. Porter,et al.  An Electron Microscope Study of the Rat Ovum , 1959, The Journal of biophysical and biochemical cytology.

[63]  M. Mason,et al.  Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. , 2001, Journal of immunological methods.

[64]  S. Oda,et al.  The gamete fusion process is defective in eggs of Cd9-deficient mice , 2000, Nature Genetics.

[65]  S. Pfeffer Transport-vesicle targeting: tethers before SNAREs , 1999, Nature Cell Biology.

[66]  E. Mekada,et al.  Requirement of CD9 on the egg plasma membrane for fertilization. , 2000, Science.

[67]  Z. Cohn,et al.  VESICLE FUSION AND FORMATION AT THE SURFACE OF PINOCYTIC VACUOLES IN MACROPHAGES , 1968, The Journal of cell biology.

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

[69]  Wesley I. Sundquist,et al.  Tsg101 and the Vacuolar Protein Sorting Pathway Are Essential for HIV-1 Budding , 2001, Cell.

[70]  L. Collinson,et al.  JCB Article , 2001 .

[71]  J. Neefjes,et al.  Recycling MHC class I molecules and endosomal peptide loading. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[72]  T. Kirchhausen,et al.  Three ways to make a vesicle , 2000, Nature Reviews Molecular Cell Biology.

[73]  J. Reimann,et al.  MHC class I-restricted CTL responses to exogenous antigens. , 1996, Immunity.

[74]  S. Fitter,et al.  Transmembrane 4 superfamily protein CD151 (PETA-3) associates with beta 1 and alpha IIb beta 3 integrins in haemopoietic cell lines and modulates cell-cell adhesion. , 1999, The Biochemical journal.

[75]  J. Skehel,et al.  Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. , 2000, Annual review of biochemistry.

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

[77]  A. Rudensky,et al.  Major Histocompatibility Complex Class II Compartments in Human and Mouse B Lymphoblasts Represent Conventional Endocytic Compartments , 1997, The Journal of cell biology.

[78]  M. Hemler,et al.  Specific tetraspanin functions , 2001, The Journal of cell biology.

[79]  F. Berditchevski,et al.  A Novel Link between Integrins, Transmembrane-4 Superfamily Proteins (CD63 and CD81), and Phosphatidylinositol 4-Kinase* , 1997, The Journal of Biological Chemistry.

[80]  M. Komada,et al.  Hrs, a FYVE finger protein localized to early endosomes, is implicated in vesicular traffic and required for ventral folding morphogenesis. , 1999, Genes & development.

[81]  P. Woodman,et al.  TSG101/Mammalian VPS23 and Mammalian VPS28 Interact Directly and Are Recruited to VPS4-induced Endosomes* , 2001, The Journal of Biological Chemistry.

[82]  I. Martinez,et al.  Synaptotagmin VII Regulates Ca2+-Dependent Exocytosis of Lysosomes in Fibroblasts , 2000, The Journal of cell biology.

[83]  S. Knight,et al.  MHC class II molecules transferred between allogeneic dendritic cells stimulate primary mixed leukocyte reactions. , 1999, International immunology.

[84]  J. Slot,et al.  Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes , 1991, The Journal of experimental medicine.

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

[86]  H. Ploegh,et al.  Major Histocompatibility Complex Class 1I Compartments in Human B Lymphoblastoid Cells Are Distinct from Early Endosomes By Peter J. Peters,* Gra~a Raposo,* Jacques J. Neefjes,~ , 1995 .

[87]  Fulvio Reggiori,et al.  Sorting of proteins into multivesicular bodies: ubiquitin‐dependent and ‐independent targeting , 2001, The EMBO journal.

[88]  V. ter meulen,et al.  CD9, a tetraspan transmembrane protein, renders cells susceptible to canine distemper virus , 1997, Journal of virology.

[89]  H. Ploegh,et al.  Major histocompatibility complex class II compartments in human B lymphoblastoid cells are distinct from early endosomes , 1995, The Journal of experimental medicine.

[90]  Z. Kam,et al.  c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. , 1998, Genes & development.

[91]  H. Stenmark,et al.  Hrs recruits clathrin to early endosomes , 2001, The EMBO journal.

[92]  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.

[93]  H. Ploegh,et al.  The tetraspanin protein CD82 associates with both free HLA class I heavy chain and heterodimeric beta 2-microglobulin complexes. , 1997, Journal of immunology.

[94]  F. Berditchevski,et al.  Generation of Monoclonal Antibodies to Integrin-associated Proteins , 1997, The Journal of Biological Chemistry.

[95]  G. Griffiths,et al.  Regulated Secretion from Hemopoietic Cells , 1999, The Journal of cell biology.

[96]  J. Tew,et al.  Follicular dendritic cells: beyond the necessity of T-cell help. , 2001, Trends in immunology.

[97]  C. Harding,et al.  Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. , 1984, European journal of cell biology.

[98]  C Caux,et al.  Immunobiology of dendritic cells. , 2000, Annual review of immunology.

[99]  H. Geuze,et al.  Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. , 2000, Journal of cell science.

[100]  M. Hemler,et al.  Evaluation of Prototype Transmembrane 4 Superfamily Protein Complexes and Their Relation to Lipid Rafts* , 2001, The Journal of Biological Chemistry.