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bioRxiv · 10.1101/2023.08.11.552954

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

El-Mansi, S.·Mitchell, T. P.·Miklavc, P.·Frick, M.·Nightingale, T. D.
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Abstract

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.

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El-Mansi, S., Mitchell, T. P., Miklavc, P., Frick, M., Nightingale, T. D.. 2023-08-12. The unconventional Myosin-1C augments endothelial secretion of von Willebrand factor by linking contractile actomyosin machinery to the plasma membrane. https://doi.org/10.1101/2023.08.11.552954

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