Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins[S]

Exosomes are bioactive vesicles released from multivesicular bodies (MVB) by intact cells and participate in intercellular signaling. We investigated the presence of lipid-related proteins and bioactive lipids in RBL-2H3 exosomes. Besides a phospholipid scramblase and a fatty acid binding protein, the exosomes contained the whole set of phospholipases (A2, C, and D) together with interacting proteins such as aldolase A and Hsp 70. They also contained the phospholipase D (PLD) / phosphatidate phosphatase 1 (PAP1) pathway leading to the formation of diglycerides. RBL-2H3 exosomes also carried members of the three phospholipase A2 classes: the calcium-dependent cPLA2-IVA, the calcium-independent iPLA2-VIA, and the secreted sPLA2-IIA and V. Remarkably, almost all members of the Ras GTPase superfamily were present, and incubation of exosomes with GTPγS triggered activation of phospholipase A2 (PLA2)and PLD2. A large panel of free fatty acids, including arachidonic acid (AA) and derivatives such as prostaglandin E2 (PGE2) and 15-deoxy-Δ12,14-prostaglandinJ2 (15-d PGJ2), were detected. We observed that the exosomes were internalized by resting and activated RBL cells and that they accumulated in an endosomal compartment. Endosomal concentrations were in the micromolar range for prostaglandins; i.e., concentrations able to trigger prostaglandin-dependent biological responses. Therefore exosomes are carriers of GTP-activatable phospholipases and lipid mediators from cell to cell.

[1]  E. Béraud,et al.  Essential role of Notch signaling in apoptosis of human pancreatic tumoral cells mediated by exosomal nanoparticles , 2009, International journal of cancer.

[2]  Graça Raposo,et al.  Exosomes--vesicular carriers for intercellular communication. , 2009, Current opinion in cell biology.

[3]  J. Scher,et al.  The Anti-Inflammatory Effects of Prostaglandins , 2009, Journal of Investigative Medicine.

[4]  J. Redondo,et al.  COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH2 for Transcellular Metabolism to PGE2 by Tumor Cells , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[5]  R. Murphy,et al.  Transcellular biosynthesis of cysteinyl leukotrienes in vivo during mouse peritoneal inflammation , 2009, Proceedings of the National Academy of Sciences.

[6]  J. Gruenberg,et al.  Molecular assemblies and membrane domains in multivesicular endosome dynamics. , 2009, Experimental cell research.

[7]  Rong-Fong Shen,et al.  Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein. , 2009, Biochemical and biophysical research communications.

[8]  S. Snyder,et al.  TRP_2, a Lipid/Trafficking Domain That Mediates Diacylglycerol-induced Vesicle Fusion* , 2008, Journal of Biological Chemistry.

[9]  Isabelle Fourquaux,et al.  Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism , 2008, Molecular Cancer Therapeutics.

[10]  L. Nagy,et al.  The many faces of PPARgamma: anti-inflammatory by any means? , 2008, Immunobiology.

[11]  J. Balsinde,et al.  Group IVA Phospholipase A2 Is Necessary for the Biogenesis of Lipid Droplets* , 2008, Journal of Biological Chemistry.

[12]  G. Raposo,et al.  Mouse neuroblastoma cells release prion infectivity associated with exosomal vesicles , 2008, Biology of the cell.

[13]  M. Gelb,et al.  Biochemistry and physiology of mammalian secreted phospholipases A2. , 2008, Annual review of biochemistry.

[14]  Sanchita Bhatnagar,et al.  Exosome Function: From Tumor Immunology to Pathogen Biology , 2008, Traffic.

[15]  S. Nagata,et al.  Identification of Tim4 as a phosphatidylserine receptor , 2007, Nature.

[16]  M. Vidal,et al.  Reticulocyte-secreted exosomes bind natural IgM antibodies: involvement of a ROS-activatable endosomal phospholipase iPLA2. , 2007, Blood.

[17]  F. Castellino,et al.  Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. , 2007, Blood.

[18]  M. Lagarde,et al.  De novo biosynthesis of the late endosome lipid, bis(monoacylglycero)phosphates⃞ Published, JLR Papers in Press, June 8, 2007. , 2007, Journal of Lipid Research.

[19]  Odile Burlet-Schiltz,et al.  Mascot File Parsing and Quantification (MFPaQ), a New Software to Parse, Validate, and Quantify Proteomics Data Generated by ICAT and SILAC Mass Spectrometric Analyses , 2007, Molecular & Cellular Proteomics.

[20]  Michalis V. Karamouzis,et al.  Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets , 2007, Nature Reviews Drug Discovery.

[21]  N. Hirashima,et al.  Munc18-2 regulates exocytotic membrane fusion positively interacting with syntaxin-3 in RBL-2H3 cells. , 2007, Molecular immunology.

[22]  A. Fomina,et al.  T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor , 2007, Journal of cellular physiology.

[23]  Federica Briatore,et al.  4-Hydroxynonenal and PPARgamma ligands affect proliferation, differentiation, and apoptosis in colon cancer cells. , 2007, Free radical biology & medicine.

[24]  J. Boyce Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation , 2007, Immunological reviews.

[25]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[26]  M. Gelb,et al.  Recombinant production and properties of binding of the full set of mouse secreted phospholipases A2 to the mouse M-type receptor. , 2007, Biochemistry.

[27]  M. Thurnher Lipids in dendritic cell biology: messengers, effectors, and antigens , 2007, Journal of leukocyte biology.

[28]  Akm A. Sattar,et al.  Cytosolic PLA2 in zymogen granule fusion and amylase release: inhibition of GTP-induced fusion by arachidonyl trifluoromethyl ketone points to cPLA2 in G-protein-mediated secretory vesicle fusion. , 2006, Journal of biochemistry.

[29]  F. G. van der Goot,et al.  Intra-endosomal membrane traffic. , 2006, Trends in cell biology.

[30]  T. Kita,et al.  Constitutive GDP/GTP Exchange and Secretion-dependent GTP Hydrolysis Activity for Rab27 in Platelets* , 2006, Journal of Biological Chemistry.

[31]  R. Murphy,et al.  Eicosanoid Transcellular Biosynthesis: From Cell-Cell Interactions to in Vivo Tissue Responses , 2006, Pharmacological Reviews.

[32]  H. Urakubo,et al.  Ca2+‐independent phospholipase A2‐dependent sustained Rho‐kinase activation exhibits all‐or‐none response , 2006, Genes to cells : devoted to molecular & cellular mechanisms.

[33]  M. Record,et al.  Selective Activation of Nuclear Phospholipase D-1 by G Protein–Coupled Receptor Agonists in Vascular Smooth Muscle Cells , 2006, Circulation research.

[34]  Noriko Kitanaka,et al.  Epidermal-type fatty acid binding protein as a negative regulator of IL-12 production in dendritic cells. , 2006, Biochemical and biophysical research communications.

[35]  S. Ryu,et al.  The phox homology domain of phospholipase D activates dynamin GTPase activity and accelerates EGFR endocytosis , 2006, Nature Cell Biology.

[36]  W. Cho,et al.  Systematic Evaluation of Transcellular Activities of Secretory Phospholipases A2 , 2006, Journal of Biological Chemistry.

[37]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[38]  D. Souza,et al.  GTP uptake into rat brain synaptic vesicles , 2006, Brain Research.

[39]  Nikos Werner,et al.  Circulating CD31+/Annexin V+ Apoptotic Microparticles Correlate With Coronary Endothelial Function in Patients With Coronary Artery Disease , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[40]  O. Nosjean,et al.  Covalent binding of 15-deoxy-delta12,14-prostaglandin J2 to PPARgamma. , 2005, Biochemical and biophysical research communications.

[41]  M. Record,et al.  Characterization of exosome subpopulations from RBL-2H3 cells using fluorescent lipids. , 2005, Blood cells, molecules & diseases.

[42]  I. Pecht,et al.  Desensitization of mast cells' secretory response to an immuno-receptor stimulus. , 2005, Immunology letters.

[43]  J. Exton,et al.  Localization and regulation of phospholipase D2 by ARF6 , 2005, Journal of cellular biochemistry.

[44]  J. Scher,et al.  15d-PGJ2: the anti-inflammatory prostaglandin? , 2005, Clinical immunology.

[45]  M. Record,et al.  PLD2 is enriched on exosomes and its activity is correlated to the release of exosomes , 2004, FEBS letters.

[46]  S. Agaugué,et al.  Secretory phospholipase A2 induces dendritic cell maturation , 2004, European journal of immunology.

[47]  C. Claudel-Renard,et al.  Human Cytomegalovirus Carries a Cell-Derived Phospholipase A2 Required for Infectivity , 2004, Journal of Virology.

[48]  Sébastien Roy,et al.  Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. , 2004, The Biochemical journal.

[49]  J. Pfeilschifter,et al.  Inhibition of Rho modulates cytokine-induced prostaglandin E2 formation in renal mesangial cells. , 2004, Biochimica et biophysica acta.

[50]  S. Baksh,et al.  Apoptotic Cells Induce Migration of Phagocytes via Caspase-3-Mediated Release of a Lipid Attraction Signal , 2003, Cell.

[51]  G. Birkenmeier,et al.  Mast Cell-Derived Exosomes Induce Phenotypic and Functional Maturation of Dendritic Cells and Elicit Specific Immune Responses In Vivo1 , 2003, The Journal of Immunology.

[52]  I. Hammel,et al.  Synaptotagmin III is a critical factor for the formation of the perinuclear endocytic recycling compartment and determination of secretory granules size , 2003, Journal of Cell Science.

[53]  M. Gelb,et al.  Interfacial Kinetic and Binding Properties of the Complete Set of Human and Mouse Groups I, II, V, X, and XII Secreted Phospholipases A2 * , 2002, The Journal of Biological Chemistry.

[54]  Peng Liu,et al.  Selective Cooperation between Fatty Acid Binding Proteins and Peroxisome Proliferator-Activated Receptors in Regulating Transcription , 2002, Molecular and Cellular Biology.

[55]  S. Ryu,et al.  Phospholipase D2 directly interacts with aldolase via Its PH domain. , 2002, Biochemistry.

[56]  R. Sakamoto,et al.  Characterization of secretory type IIA phospholipase A2 (sPLA2-IIA) as a glycyrrhizin (GL)-binding protein and the GL-induced inhibition of the CK-II-mediated stimulation of sPLA2-IIA activity in vitro. , 2001, Biological & pharmaceutical bulletin.

[57]  N. Hirashima,et al.  Dynamics of intracellular granules with CD63-GFP in rat basophilic leukemia cells. , 2001, Journal of biochemistry.

[58]  H. Brown,et al.  Interaction of phospholipase D1 with a casein-kinase-2-like serine kinase. , 2001, The Biochemical journal.

[59]  M. Hemler,et al.  FPRP, a Major, Highly Stoichiometric, Highly Specific CD81- and CD9-associated Protein* , 2001, The Journal of Biological Chemistry.

[60]  M. Bader,et al.  Phospholipase D in rat myometrium: occurrence of a membrane-bound ARF6 (ADP-ribosylation factor 6)-regulated activity controlled by betagamma subunits of heterotrimeric G-proteins. , 2000, The Biochemical journal.

[61]  R. Gross,et al.  The Genomic Organization, Complete mRNA Sequence, Cloning, and Expression of a Novel Human Intracellular Membrane-associated Calcium-independent Phospholipase A2 * , 2000, The Journal of Biological Chemistry.

[62]  M. Murakami,et al.  Regulation of type V phospholipase A2 expression and function by proinflammatory stimuli. , 1999, European journal of biochemistry.

[63]  K. Shinozaki,et al.  A novel phosphatidylglycerol-selective phospholipase A2 from macrophages. , 1999, Biochemistry.

[64]  C. Bae,et al.  Determination of Interaction Sites on the Small G Protein RhoA for Phospholipase D* , 1998, The Journal of Biological Chemistry.

[65]  C. Hess,et al.  Ectosomes released by human neutrophils are specialized functional units. , 1998, Journal of immunology.

[66]  R. Parton,et al.  A lipid associated with the antiphospholipid syndrome regulates endosome structure and function , 1998, Nature.

[67]  R. A. Blackwood,et al.  Phospholipase D activity facilitates Ca2+-induced aggregation and fusion of complex liposomes. , 1997, The American journal of physiology.

[68]  J. Sikela,et al.  Human chromosome 1 localization of the gene for a prostaglandin F2α, receptor negative regulatory protein , 1996, Human Genetics.

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

[70]  W. J. Blitterswijk,et al.  Rapid attenuation of receptor‐induced diacylglycerol and phosphatidic acid by phospholipase D‐mediated transphosphatidylation: formation of bisphosphatidic acid. , 1993, The EMBO journal.

[71]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[72]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[73]  P. Gierschik,et al.  In vitro reconstitution of activation of PLCepsilon by Ras and Rho GTPases. , 2009, Methods in molecular biology.

[74]  P. Gierschik,et al.  In vitro Reconstitution of Activation of PLCε by Ras and Rho GTPases , 2009 .

[75]  K. Reue,et al.  Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism , 2008 .

[76]  Inhibition of (cid:1) -secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes , 2022 .