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

El-Mansi, Sammy; Mitchell, Tom P; Mobyen, Golzar; McKinnon, Thomas A. J.; Miklavc, Pika; Frick, Manfred; Nightingale, Thomas D; McKinnon, Thomas AJ; McKinnon, Thomas Aj

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 the WPB 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 the unconventional myosin-1C (Myo1c) is recruited post-fusion via its pleckstrin homology domain in an actin-independent process. This provides a link between the actin ring and phosphatidylinositol 4,5-bisphosphate (PIP2) at the membrane of the fused organelle and is necessary to ensure maximal VWF secretion. This is an active process requiring Myo1c ATPase activity as inhibition of class I myosins using the inhibitor Pentachloropseudilin or expression of an ATPase deficient Myo1c rigor mutant perturbs the expulsion of VWF and alters the kinetics of the exocytic actin ring. These data offer a novel insight into the control of an essential physiological process and provide a new way in which it can be regulated. [Abstract copyright: Copyright © 2024 American Society of Hematology.]

Citation

El-Mansi, S., Mitchell, T. P., Mobyen, G., McKinnon, T. A. J., Miklavc, P., Frick, M., …McKinnon, T. A. (in press). Myosin-1C augments secretion of von Willebrand factor by linking contractile actomyosin machinery to the plasma membrane. #Journal not on list, https://doi.org/10.1182/bloodadvances.2024012590

• Journal Article Type: Article
• Acceptance Date: Apr 16, 2024
• Online Publication Date: Apr 26, 2024
• Deposit Date: May 21, 2024
• Publicly Available Date: May 21, 2024
• Journal: Blood advances
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1182/bloodadvances.2024012590