title: Myosin Va acts in concert with Rab27a and MyRIP to regulate acute von-Willebrand factor release from endothelial cells.
abstract: Von-Willebrand factor (vWF) is a highly multimerized hemostatic glycoprotein that is stored in endothelial Weibel-Palade bodies (WPB) and secreted upon cell stimulation to act in recruiting platelets to sites of vessel injury. Only fully matured multimeric vWF represents an efficient anchor for platelets, and endothelial cells have developed mechanisms to prevent release of immature vWF. Full maturation of vWF occurs within WPB following their translocation from a perinuclear site of emergence at the trans-Golgi network (TGN) to the cell periphery. The WPB-associated small GTPase Rab27a is involved in restricting immature WPB exocytosis and we searched for links between Rab27a and the actin cytoskeleton that could anchor WPB inside endothelial cells until they are fully matured. We here identify myosin Va as such link. Myosin Va forms a tripartite complex with Rab27a and its effector MyRIP and depletion of or dominant-negative interference with myosin Va leads to an increase in the ratio of perinuclear to more peripheral WPB. Concomitantly, myosin Va depletion results in an elevated secretion of less-oligomeric vWF from histamine-stimulated endothelial cells. These results indicate that a Rab27a/MyRIP/myosin Va complex is involved in linking WPB to the peripheral actin cytoskeleton of endothelial cells to allow full maturation and prevent premature secretion of vWF.
authors: Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Münster, Münster, Germany.
authors: Inés
authors: I
authors: Rojo Pulido
authors: Thomas D
authors: TD
authors: Nightingale
authors: François
authors: F
authors: Darchen
authors: Miguel C
authors: MC
authors: Seabra
authors: Daniel F
authors: DF
authors: Cutler
authors: Volker
authors: V
authors: Gerke
mesh_terms: D018929:Cell Culture Techniques; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D018995:Myosin Heavy Chains / Q000235:genetics / Q000502:physiology*; D024701:Myosin Type V / Q000235:genetics / Q000502:physiology*; D010957:Plasmids; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000075745:rab27 GTP-Binding Proteins; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: C501262:MYRIP protein, human; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; D014841:von Willebrand Factor; C077511:MYO5A protein, human; D024701:Myosin Type V; C066694:RAB27A protein, human; D018995:Myosin Heavy Chains; D020691:rab GTP-Binding Proteins