Figure 3.

Model of membrane dynamics during Weibel-Palade body (WPB) biogenesis. WPB biogenesis begins with the assembly of tubular multimers of von Willebrand factor (vWF) in the Golgi. The quantal length of the multimers is limited by the length of the Golgi cisterna within an individual stack, the size of which is controlled by RAB6A; vWF multimer quanta are then assembled into longer tubules depending on the integrity of the Golgi ribbon. Immature WPBs encasing vWF tubules bud from the Golgi in a process requiring AP-1 and clathrin, and then mature by fusion with vesicles bearing CD63 and the vSNARE, VAMP8, originating from early endosomes in an AP-3-dependent process. BLOC-2 also contributes to WPB maturation in as yet unknown ways. Small WPBs are secreted basolaterally. By contrast, maturing large WPBs are transported to the apical plasma membrane of endothelial cells along microtubules and tethered to the plasma membrane through the action of the RAB27A/ MyRIP/ MyosinVa complex. Mature WPBs are decorated by several RABs (e.g. RAB3, 15, 33 and 37), some of which (e.g. RAB3 and RAB15) might positively regulate the release step. Apical secretion of large WPBs (Box) requires actin polymerization at the basal tip mediated by Annexin A2, calcium-dependent tethering mediated by MUNC13–4, and fusion mediated by the Syntaxin 4/ SNAP-23 tSNARE and either VAMP3 or VAMP8 as the vSNARE. The latter step is facilitated by STXBP3 (Munc18c) and antagonized by STXBP5.