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Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells

Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function...

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Autores principales: Lopes da Silva, Mafalda, O'Connor, Marie N., Kriston-Vizi, Janos, White, Ian J., Al-Shawi, Raya, Simons, J. Paul, Mössinger, Julia, Haucke, Volker, Cutler, Daniel F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878995/
https://www.ncbi.nlm.nih.gov/pubmed/27068535
http://dx.doi.org/10.1242/jcs.187864
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author Lopes da Silva, Mafalda
O'Connor, Marie N.
Kriston-Vizi, Janos
White, Ian J.
Al-Shawi, Raya
Simons, J. Paul
Mössinger, Julia
Haucke, Volker
Cutler, Daniel F.
author_facet Lopes da Silva, Mafalda
O'Connor, Marie N.
Kriston-Vizi, Janos
White, Ian J.
Al-Shawi, Raya
Simons, J. Paul
Mössinger, Julia
Haucke, Volker
Cutler, Daniel F.
author_sort Lopes da Silva, Mafalda
collection PubMed
description Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIα and PI4KIIβ in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIα-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function.
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spelling pubmed-48789952016-07-14 Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells Lopes da Silva, Mafalda O'Connor, Marie N. Kriston-Vizi, Janos White, Ian J. Al-Shawi, Raya Simons, J. Paul Mössinger, Julia Haucke, Volker Cutler, Daniel F. J Cell Sci Research Article Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIα and PI4KIIβ in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIα-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function. The Company of Biologists Ltd 2016-05-15 /pmc/articles/PMC4878995/ /pubmed/27068535 http://dx.doi.org/10.1242/jcs.187864 Text en © 2016. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Lopes da Silva, Mafalda
O'Connor, Marie N.
Kriston-Vizi, Janos
White, Ian J.
Al-Shawi, Raya
Simons, J. Paul
Mössinger, Julia
Haucke, Volker
Cutler, Daniel F.
Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
title Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
title_full Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
title_fullStr Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
title_full_unstemmed Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
title_short Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells
title_sort type ii pi4-kinases control weibel-palade body biogenesis and von willebrand factor structure in human endothelial cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878995/
https://www.ncbi.nlm.nih.gov/pubmed/27068535
http://dx.doi.org/10.1242/jcs.187864
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