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PMID: 22660413 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.

Nature cell biology ·Vol. 14 ·No. 7 ·2012-06-03 ·Pages 677-85

Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G

Abstract

The biogenesis of exosomes, small secreted vesicles involved in signalling processes, remains incompletely understood. Here, we report evidence that the syndecan heparan sulphate proteoglycans and their cytoplasmic adaptor syntenin control the formation of exosomes. Syntenin interacts directly with ALIX through LYPX(n)L motifs, similarly to retroviral proteins, and supports the intraluminal budding of endosomal membranes. Syntenin exosomes depend on the availability of heparan sulphate, syndecans, ALIX and ESCRTs, and impact on the trafficking and confinement of FGF signals. This study identifies a key role for syndecan-syntenin-ALIX in membrane transport and signalling processes.

MeSH Terms
Animals Binding Sites Calcium-Binding Proteins/genetics,metabolism Cell Cycle Proteins/genetics,metabolism Cell Line, Tumor Endosomal Sorting Complexes Required for Transport/genetics,metabolism Exosomes/metabolism Fibroblast Growth Factors/metabolism Heparitin Sulfate/metabolism Humans Mice Protein Interaction Domains and Motifs Protein Transport RNA Interference Receptors, Fibroblast Growth Factor/metabolism Recombinant Fusion Proteins/metabolism Signal Transduction Syndecans/genetics,metabolism Syntenins/genetics,metabolism Time Factors Transfection
Chemicals
Calcium-Binding Proteins Cell Cycle Proteins Endosomal Sorting Complexes Required for Transport PDCD6IP protein, human Pdcd6ip protein, mouse Receptors, Fibroblast Growth Factor Recombinant Fusion Proteins Syndecans Syntenins Fibroblast Growth Factors Heparitin Sulfate
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Baietti Maria Francesca
Laboratory for Glycobiology and Developmental Genetics, Department of Human Genetics, KULeuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Zhang Zhe
Mortier Eva
Melchior Aurélie
Degeest Gisèle
Geeraerts Annelies
Ivarsson Ylva
Depoortere Fabienne
Coomans Christien
Vermeiren Elke
Zimmermann Pascale
David Guido
References (60)
60 references, click to expand
  1. A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses.
    Nat Neurosci. 2011 Oct 02;14(11):1421-9 PMID: 21964490
  2. Exosomes: endosomal-derived vesicles shipping extracellular messages.
    Curr Opin Cell Biol. 2004 Aug;16(4):415-21 PMID: 15261674
  3. ExoCarta: A compendium of exosomal proteins and RNA.
    Proteomics. 2009 Nov;9(21):4997-5000 PMID: 19810033
  4. Inhibition of rab5 GTPase activity stimulates membrane fusion in endocytosis.
    EMBO J. 1994 Mar 15;13(6):1287-96 PMID: 8137813
  5. Depletion of TSG101 forms a mammalian "Class E" compartment: a multicisternal early endosome with multiple sorting defects.
    J Cell Sci. 2005 Jul 15;118(Pt 14):3003-17 PMID: 16014378
  6. Membrane heparan sulfate proteoglycan-supported FGF2-FGFR1 signaling: evidence in support of the "cooperative end structures" model.
    J Biol Chem. 2001 Nov 9;276(45):41921-9 PMID: 11551944
  7. Multiple distinct membrane heparan sulfate proteoglycans in human lung fibroblasts.
    J Biol Chem. 1989 Apr 25;264(12):7009-16 PMID: 2523387
  8. Beyond Tsg101: the role of Alix in 'ESCRTing' HIV-1.
    Nat Rev Microbiol. 2007 Dec;5(12):912-6 PMID: 17982468
  9. The signaling mechanisms of syndecan heparan sulfate proteoglycans.
    Curr Opin Cell Biol. 2009 Oct;21(5):662-9 PMID: 19535238
  10. Syntenin, a PDZ protein that binds syndecan cytoplasmic domains.
    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13683-8 PMID: 9391086
  11. Syntenin-syndecan binding requires syndecan-synteny and the co-operation of both PDZ domains of syntenin.
    J Biol Chem. 2000 Jun 30;275(26):19933-41 PMID: 10770943
  12. The P4-ATPase TAT-5 inhibits the budding of extracellular vesicles in C. elegans embryos.
    Curr Biol. 2011 Dec 6;21(23):1951-9 PMID: 22100064
  13. Structural and functional studies of ALIX interactions with YPX(n)L late domains of HIV-1 and EIAV.
    Nat Struct Mol Biol. 2008 Jan;15(1):43-9 PMID: 18066081
  14. Characterization of syntenin, a syndecan-binding PDZ protein, as a component of cell adhesion sites and microfilaments.
    Mol Biol Cell. 2001 Feb;12(2):339-50 PMID: 11179419
  15. The ESCRT pathway.
    Dev Cell. 2011 Jul 19;21(1):77-91 PMID: 21763610
  16. Exosomes: composition, biogenesis and function.
    Nat Rev Immunol. 2002 Aug;2(8):569-79 PMID: 12154376
  17. Rab7 regulates late endocytic trafficking downstream of multivesicular body biogenesis and cargo sequestration.
    J Biol Chem. 2009 May 1;284(18):12110-24 PMID: 19265192
  18. Clustering induces redistribution of syndecan-4 core protein into raft membrane domains.
    J Biol Chem. 2002 May 31;277(22):19946-51 PMID: 11889131
  19. Host factors involved in retroviral budding and release.
    Nat Rev Microbiol. 2011 Jun 16;9(7):519-31 PMID: 21677686
  20. Ephrin-B1 and ephrin-B2 mediate EphB-dependent presynaptic development via syntenin-1.
    Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20487-92 PMID: 19915143
  21. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein.
    Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):4146-51 PMID: 22315426
  22. Molecular cloning of amphiglycan, a novel integral membrane heparan sulfate proteoglycan expressed by epithelial and fibroblastic cells.
    J Cell Biol. 1992 Aug;118(4):961-9 PMID: 1500433
  23. Ceramide triggers budding of exosome vesicles into multivesicular endosomes.
    Science. 2008 Feb 29;319(5867):1244-7 PMID: 18309083
  24. Syndecan recycling [corrected] is controlled by syntenin-PIP2 interaction and Arf6.
    Dev Cell. 2005 Sep;9(3):377-88 PMID: 16139226
  25. Membrane budding and scission by the ESCRT machinery: it's all in the neck.
    Nat Rev Mol Cell Biol. 2010 Aug;11(8):556-66 PMID: 20588296
  26. Heparan sulphate proteoglycans: the sweet side of development.
    Nat Rev Mol Cell Biol. 2005 Jul;6(7):530-41 PMID: 16072037
  27. Dynamics of ESCRT protein recruitment during retroviral assembly.
    Nat Cell Biol. 2011 Apr;13(4):394-401 PMID: 21394083
  28. ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1.
    Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):E559-68 PMID: 21825135
  29. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes.
    Nature. 2010 Apr 8;464(7290):864-9 PMID: 20305637
  30. ATPase-defective mammalian VPS4 localizes to aberrant endosomes and impairs cholesterol trafficking.
    Mol Biol Cell. 2000 Jan;11(1):227-39 PMID: 10637304
  31. Rab conversion as a mechanism of progression from early to late endosomes.
    Cell. 2005 Sep 9;122(5):735-49 PMID: 16143105
  32. The multiple personalities of Alix.
    J Cell Sci. 2006 Aug 1;119(Pt 15):3025-32 PMID: 16868030
  33. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
    Nat Cell Biol. 2007 Jun;9(6):654-9 PMID: 17486113
  34. Structural basis for viral late-domain binding to Alix.
    Nat Struct Mol Biol. 2007 Mar;14(3):194-9 PMID: 17277784
  35. Syntenin-1 is a new component of tetraspanin-enriched microdomains: mechanisms and consequences of the interaction of syntenin-1 with CD63.
    Mol Cell Biol. 2006 Oct;26(20):7707-18 PMID: 16908530
  36. Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes.
    PLoS Biol. 2007 Jun;5(6):e158 PMID: 17550307
  37. Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation.
    Mol Biol Cell. 2006 Aug;17(8):3469-83 PMID: 16707569
  38. Requirement of heparan sulfate for bFGF-mediated fibroblast growth and myoblast differentiation.
    Science. 1991 Jun 21;252(5013):1705-8 PMID: 1646484
  39. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins.
    Nature. 2009 Mar 26;458(7237):445-52 PMID: 19325624
  40. Heparan sulphate proteoglycans fine-tune mammalian physiology.
    Nature. 2007 Apr 26;446(7139):1030-7 PMID: 17460664
  41. Transmembrane signaling proteoglycans.
    Annu Rev Cell Dev Biol. 2010;26:89-114 PMID: 20565253
  42. Cell biology: The ins and outs of exosomes.
    Science. 2005 Jun 24;308(5730):1862-3 PMID: 15976285
  43. Role of LBPA and Alix in multivesicular liposome formation and endosome organization.
    Science. 2004 Jan 23;303(5657):531-4 PMID: 14739459
  44. PIP(2)-PDZ domain binding controls the association of syntenin with the plasma membrane.
    Mol Cell. 2002 Jun;9(6):1215-25 PMID: 12086619
  45. A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis.
    Dev Cell. 2006 Mar;10(3):343-54 PMID: 16516837
  46. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells.
    Nat Cell Biol. 2008 May;10(5):619-24 PMID: 18425114
  47. Synergistic control of cell adhesion by integrins and syndecans.
    Nat Rev Mol Cell Biol. 2007 Dec;8(12):957-69 PMID: 17971838
  48. Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling.
    J Biol Chem. 2003 Dec 5;278(49):48651-7 PMID: 14504279
  49. Cooperative phosphoinositide and peptide binding by PSD-95/discs large/ZO-1 (PDZ) domain of polychaetoid, Drosophila zonulin.
    J Biol Chem. 2011 Dec 30;286(52):44669-78 PMID: 22033935
  50. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73.
    J Cell Biol. 1999 Nov 1;147(3):599-610 PMID: 10545503
  51. The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans.
    J Cell Biol. 2006 Jun 19;173(6):949-61 PMID: 16785323
  52. MVB vesicle formation: ESCRT-dependent, ESCRT-independent and everything in between.
    Curr Opin Cell Biol. 2011 Aug;23(4):452-7 PMID: 21570275
  53. The ins and outs of syntenin, a multifunctional intracellular adaptor protein.
    J Cell Sci. 2008 May 1;121(Pt 9):1349-55 PMID: 18434645
  54. How HIV-1 hijacks ALIX.
    Nat Struct Mol Biol. 2007 Apr;14(4):254-6 PMID: 17410087
  55. Decoding the intrinsic mechanism that prohibits ALIX interaction with ESCRT and viral proteins.
    Biochem J. 2010 Dec 15;432(3):525-34 PMID: 20929444
  56. The postsynaptic density 95/disc-large/zona occludens protein syntenin directly interacts with frizzled 7 and supports noncanonical Wnt signaling.
    Mol Biol Cell. 2008 Apr;19(4):1594-604 PMID: 18256285
  57. ESCRT-III protein requirements for HIV-1 budding.
    Cell Host Microbe. 2011 Mar 17;9(3):235-242 PMID: 21396898
  58. Exosome secretion: molecular mechanisms and roles in immune responses.
    Traffic. 2011 Dec;12(12):1659-68 PMID: 21645191
  59. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization.
    Mol Cell. 2000 Sep;6(3):743-50 PMID: 11030354
  60. Multivesicular endosome biogenesis in the absence of ESCRTs.
    Traffic. 2009 Jul;10(7):925-37 PMID: 19490536
Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2502
Published
2012-06-03
Epub
2012-00-03
Pages
677-85
Language
English
Region
England
NLM ID
100890575
Subset
IM
Corrections
CommentIn
PMID: 22743708
External Links
PubMed source DOI: 10.1038/ncb2502 View journal details
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