BLOC-2 subunit HPS6 deficiency affects the tubulation and secretion of von Willebrand factor from mouse endothelial cells

Jing Ma,Zhe Zhang,Lin Yang,Janos Kriston-Vizi,Daniel F Cutler,Wei Li

doi:10.1016/j.jgg.2016.09.007

Abstract

Hermansky-Pudlak syndrome (HPS) is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies (WPBs) are members of lysosome-related organelles (LROs) whose formation is regulated by HPS protein associated complexes such as BLOC (biogenesis of lysosome-related organelles complex) -1, -2, -3, AP-3 (adaptor protein complex-3) and HOPS (homotypic fusion and protein sorting complex). Von Willebrand factor (VWF) is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin (DDAVP) stimulation in HPS1 (BLOC-3 subunit), HPS6 (BLOC-2 subunit), and HPS9 (BLOC-1 subunit) deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.

Highlights

Weibel-Palade bodies (WPBs) are secretory organelles in endothelial cells
The secretion patterns of von Willebrand factor (VWF) multimers under non-stimulated status (Fig. 1AeD, at each 00 lane) were almost normal in those three mutant mice. This indicated that only the stimulated secretion of VWF but not the basal or constitutive secretion of VWF was affected in pa, ru, and ep deficient mice
These data suggest that different Hermansky-Pudlak syndrome (HPS) proteins act differentially in VWF release, implying differential functions in WPB biogenesis and/or exocytosis

Summary

Introduction

Weibel-Palade bodies (WPBs) are secretory organelles in endothelial cells. They are large elongated rod shaped granules surrounded by a limiting membrane, with an internal tubular structure visible by electron microscopy (EM) (Weibel and Palade, 1964). At secretagogue-triggered exocytosis, the VWF multimer unfurls into the flowing plasma as a long filament, highly active in platelet recruitment. VWF tubulation and multimerization as well as the length of WPB are essential to the formation of long platelet-catching strings (Michaux et al, 2006; Nightingale et al, 2009; Ferraro et al, 2014)

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Results

Conclusion