AUTHOR=Lu Jiran , Ma Jing , Hao Zhenhua , Li Wei 

TITLE=HPS6 Regulates the Biogenesis of Weibel–Palade Body in Endothelial Cells Through Trafficking v-ATPase to Its Limiting Membrane

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.743124

DOI=10.3389/fcell.2021.743124

ISSN=2296-634X

ABSTRACT=Weibel-Palade body (WPB) is one of the lysosome-related organelles (LROs) in endothelial cells, whose main content is von Willebrand factor (vWF). Biogenesis of LROs is regulated by the Hermansky-Pudlak syndrome (HPS) protein associated complexes (HPACs) through transporting cargo proteins to WPBs. Our previous studies have shown that HPS6, a subunit of BLOC-2 complex, is likely involved in the maturation of WPBs. However, the underlying mechanism remains unknown. In this study, we found that knockdown of HPS6 in human umbilical vein endothelial cells (HUVECs) resulted in miss-shaped WPBs, decreased WPB number, and impaired vWF tubulation, which is similar to the characteristics of HPS6 deficient mouse endothelial cells. We observed similar morphological changes of WPBs in HUVECs after knockdown of ATP6V0D1 (a subunit of v-ATPase). Furthermore, we found that HPS6 interacted with ATP6V0D1, suggesting that HPS6 transports ATP6V0D1 to the WPB limiting membrane for the assembly of the v-ATPase complex to maintain its acidic luminal pH, which is critical for the formation of vWF tubules during WPB maturation. In conclusion, HPS6 likely regulates the biogenesis of WPBs by participating in the trafficking of v-ATPase to the WPB membrane.