The unconventional Myosin-1C augments endothelial secretion of von Willebrand factor by linking contractile actomyosin machinery to the plasma membrane

Blood endothelial cells control the hemostatic and inflammatory response by secreting von Willebrand factor (VWF) and P-selectin from storage organelles called Weibel-Palade bodies (WPB). Actin-associated motor proteins regulate this secretory pathway at multiple points. Prior to fusion, myosin Va forms a complex that anchors WPBs to peripheral actin structures allowing maturation of content. Post-fusion, an actomyosin ring/coat is recruited and compresses to forcibly expel the largest VWF multimers. Here we provide the first evidence for the involvement of class I myosins during regulated VWF secretion. We show that unconventional myosin-1C (Myo1c) is recruited post fusion via its pleckstrin homology domain in an actin-independent process providing a link between the actin ring and phosphatidylinositol 4,5-bisphosphate (PIP2) at the membrane of the fused organelle. This is necessary to ensure maximal VWF secretion in response to secretagogue stimulation. Inhibition of class I myosins using the inhibitor Pentachloropseudilin alters the kinetics of the exocytic actin ring. These data offer new insight into the control of an essential physiological process and provide a new potential way in which it might be therapeutically controlled. SIGNFICANCE STATEMENTMyosin motors play diverse roles in regulated secretion. In endothelial cells, the role of conventional myosins (e.g. non-muscle myosin II) are well described however little is known about the requirement of unconventional myosins. Our data identify an important function of the class 1 myosin, Myosin-1C, in the actomyosin mediated expulsion of an essential blood clotting factor (von Willebrand factor) from endothelial cells. This is the first description of how class 1 myosins contribute to primary hemostasis and is therefore greatly improves our understanding of a fundamental physiological process.