The P4-ATPase TAT-5 Inhibits the Budding of Extracellular Vesicles in C. Elegans Embryos

Curr Biol. 2011 Dec 6;21(23):1951-9. doi: 10.1016/j.cub.2011.10.040. Epub 2011 Nov 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Animals, Genetically Modified
  • Cadherins / metabolism
  • Caenorhabditis elegans / embryology*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Adhesion / physiology
  • Cell Lineage
  • Cell-Derived Microparticles / metabolism
  • Cell-Derived Microparticles / physiology*
  • Embryo, Nonmammalian / enzymology*
  • Histological Techniques
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Models, Biological*
  • Morphogenesis / genetics
  • Morphogenesis / physiology
  • Neural Cell Adhesion Molecules / metabolism
  • Oligonucleotides / genetics
  • RNA Interference

Substances

  • Cadherins
  • Caenorhabditis elegans Proteins
  • Neural Cell Adhesion Molecules
  • Oligonucleotides
  • SAX-7 protein, C elegans
  • hmr-1 protein, C elegans
  • Adenosine Triphosphatases
  • TAT-5 protein, C elegans