New kid on the BLOC

In this issue of Blood, Sharda et al show an unexpected role for biogenesis of lysosomal related organelle 2 (BLOC-2) in the formation of Weibel-Palade bodies (WPBs), a crucial storage compartment for hemostatic and inflammatory cargo in endothelial cells.1 The BLOC-2 complex is composed of 3 distinct subunits, HPS3, HPS5, and HPS6, which are absent in patients suffering from corresponding subtypes of Hermansky-Pudlak syndrome (types 3, 5, and 6).2 Patients with mutations in 1 of the BLOC-2 subunits have a severe bleeding tendency, consistent with the aberrant generation of storage compartments in platelets and endothelial cells.3 Ultrastructural analysis of platelets from patients with BLOC-2 deficiency revealed that BLOC-2 is crucial for the generation of dense, but not a granules in platelets.4 Similarly, studies focusing on the endothelial storage compartment in “ruby eye” (HPS6-deficient) mice showed an altered tubular organization of von Willebrand factor (VWF), which resulted in short and round WPBs releasing smaller VWF filaments.5 The current study confirms the effect of HPS6 on WPB morphology and provides evidence for the crucial role of BLOC-2 in CD63 trafficking to WPBs. CD63 is a notorious “late arrival” during WPB maturation because it is only trafficked to WPBs once they have budded from the trans-Golgi network.6,7 CD63 transport to WPBs is dependent on the integrity of the AP-3 complex.7,8 Very elegant cryo-EM studies have shown that CD63 resides in membrane bound luminal vesicles within WPBs.9