Evoked Weibel-Palade Body Exocytosis Modifies the Endothelial Cell Surface by Releasing a Substrate-Selective Phosphodiesterase

Weibel Palade bodies (WPB) are lysosome-related secretory organelles of endothelial cells. Commonly known for their main cargo, the platelet and leukocyte receptors von-Willebrand factor (VWF) and P-selectin, WPB play a crucial role in hemostasis and inflammation. Here, the authors identify the glycerophosphodiester phosphodiesterase domain-containing protein 5 (GDPD5) as a WPB cargo protein and show that GDPD5 is transported to WPB following uptake from the plasma membrane via an unique endocytic transport route. GDPD5 cleaves GPI-anchored, plasma membrane-resident proteins within their GPI-motif, thereby regulating their local activity. The authors identify a novel target of GDPD5 , the complement regulator CD59, and show that it is released from the endothelial surface by GDPD5 following WPB exocytosis. This results in increased deposition of complement components and can enhance local inflammatory and thrombogenic responses. Thus, stimulus-induced WPB exocytosis can modify the endothelial cell surface by GDPD5-mediated selective release of a subset of GPI-anchored proteins. Weibel-Palade bodies (WPB) are unique secretory organelles of endothelial cells. A new WPB constituent is identified, the glycerophosphodiester phosphodiesterase domain-containing protein 5 (GDPD5) and it is shown that GDPD5 is released to the cell surface upon stimulation of WPB exocytosis. Following release GDPD5 cleaves a subset of cell surface GPI-anchored proteins and CD59 is identified as one of the GDPD5 targets . image