The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story

Abstract

von Willebrand factor (VWF) plays key roles in both primary and secondary hemostasis by capturing platelets and chaperoning clotting factor VIII, respectively. It is stored within the Weibel-Palade bodies (WPBs) of endothelial cells as a highly prothrombotic protein, and its release is thus necessarily under tight control. Regulating the secretion of VWF involves multiple layers of cellular machinery that act together at different stages, leading to the exocytic fusion of WPBs with the plasma membrane and the consequent release of VWF. This review aims to provide a snapshot of the current understanding of those components, in particular the members of the Rab family, acting in the increasingly complex story of VWF secretion.

Keywords: Rab GTPase; Weibel-Palade bodies; endothelial cells; exocytosis; hemostasis; von Willebrand factor.

Fig 1

Formation and function of Weibel–Palade bodies (WPBs): focus on Rabs and their effectors. (1) The biogenesis of WPBs begins at the trans-Golgi network, where tubules of von Willebrand factor (VWF) are inserted into the nascent storage organelle. This process is dependent on the presence of a clathrin coat and the adaptor protein AP-1. Inhibition of either of these proteins results in a failure to form WPBs and constitutive secretion of VWF (normally negligible). AP-1 also recruits the tripartite complex of aftipilin, p200, and γ-synergin, which is required (presumably by the recruitment of as yet unknown proteins) for the regulated release of VWF. Rab10 is also required for the rapid regulated release of at least some VWF by a currently unknown mechanism. (2) Immature WPBs are trafficked by an as yet uncharacterized kinesin(s) to the periphery of the cell along microtubules. (3) Immature WPBs can become anchored on F-actin by a tripartite complex consisting of Rab27a, myosin and Rab27a-interacting protein (MyRIP), and myosin Va (MyoVa), and this allows peripheral localization and maturation (further multimerization of VWF, condensation of tubules, and an increase in WPB length) of the WPBs for later regulated release; alternatively, the immature WPBs are released basally at the cell surface, resulting in relatively short strings of VWF. WPBs also recruit Rab3B/Rab3D and the Rab27a/Rab3 effector Slp4a (granuphilin), as well as Rab15 and the Rab27a/Rab15 effector Munc13-4. (4) Following secretagogue stimulation, anchoring on actin is lost, and a Rab27a-dependent, Rab15-dependent and Munc13-4-dependent step at the cell surface is required for exocytosis to occur (potentially via an interaction with Doc2α). (5) A Rab27a-dependent and Slp4a-dependent docking step is necessary for release (potentially via an interaction with syntaxin or Munc18-1/Munc18-2). (6) VWF is released as high molecular weight strings at the cell surface in a manner that is expedited by the contraction of a ring of actin.