title: The P4-ATPase TAT-5 inhibits the budding of extracellular vesicles in C. elegans embryos.
abstract: BACKGROUND
  Cells release extracellular vesicles (ECVs) that can influence differentiation, modulate the immune response, promote coagulation, and induce metastasis. Many ECVs form by budding outwards from the plasma membrane, but the molecules that regulate budding are unknown. In ECVs, the outer leaflet of the membrane bilayer contains aminophospholipids that are normally sequestered to the inner leaflet of the plasma membrane, suggesting a role for lipid asymmetry in ECV budding.
  
  
  RESULTS
  We show that loss of the conserved P4-ATPase TAT-5 causes the large-scale shedding of ECVs and disrupts cell adhesion and morphogenesis in Caenorhabditis elegans embryos. TAT-5 localizes to the plasma membrane and its loss results in phosphatidylethanolamine exposure on cell surfaces. We show that RAB-11 and endosomal sorting complex required for transport (ESCRT) proteins, which regulate the topologically analogous process of viral budding, are enriched at the plasma membrane in tat-5 embryos, and are required for ECV production.
  
  
  CONCLUSIONS
  TAT-5 is the first protein identified to regulate ECV budding. TAT-5 provides a potential molecular link between loss of phosphatidylethanolamine asymmetry and the dynamic budding of vesicles from the plasma membrane, supporting the hypothesis that lipid asymmetry regulates budding. Our results also suggest that viral budding and ECV budding may share common molecular mechanisms.
authors.affiliation: Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Wehman
authors.forename: Corey
authors.initials: C
authors.lastname: Poggioli
authors.forename: Peter
authors.initials: P
authors.lastname: Schweinsberg
authors.forename: Barth D
authors.initials: BD
authors.lastname: Grant
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nance
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D015820:Cadherins / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D019070:Cell Lineage; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000201:enzymology*; D006652:Histological Techniques; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D034622:RNA Interference
chemical_list: D015820:Cadherins; D029742:Caenorhabditis elegans Proteins; D019006:Neural Cell Adhesion Molecules; D009841:Oligonucleotides; C501528:SAX-7 protein, C elegans; C450060:hmr-1 protein, C elegans; D000251:Adenosine Triphosphatases; C571176:TAT-5 protein, C elegans
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