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 Blood, 26 March 2009, Vol. 113, No. 13, pp. 3102-3109.
Prepublished online as a Blood First Edition Paper on December 16, 2008; DOI 10.1182/blood-2008-05-159699.

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THROMBOSIS AND HEMOSTASIS

Intracellular cotrafficking of factor VIII and von Willebrand factor type 2N variants to storage organelles

Maartje van den Biggelaar1,2, Alexander B. Meijer1,2, Jan Voorberg1,3, and Koen Mertens1,2

1 Department of Plasma Proteins, Sanquin Research, Amsterdam; 2 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht; and 3 Landsteiner Laboratory of AMC and Sanquin, University of Amsterdam, Amsterdam, The Netherlands

Weibel-Palade bodies (WPBs) are the endothelial storage organelles that are formed upon von Willebrand factor (VWF) expression. Apart from VWF, WPBs contain a variety of hemostatic and inflammatory proteins. Some of these are thought to be targeted to WPBs by directly interacting with VWF in the secretory pathway. Previous studies have demonstrated that coexpression of factor VIII (FVIII) with VWF results in costorage of both proteins. However, whether cotrafficking is driven by intracellular FVIII-VWF assembly has remained unclear. We now have addressed this issue using recombinant VWF type 2N variants that are known to display reduced FVIII binding in the circulation. Binding studies using purified fluorescent FVIII and VWF type 2N variants revealed FVIII binding defects varying from moderate (Arg854Gln, Cys1060Arg) to severe (Arg763Gly, Thr791Met, Arg816Trp). Upon expression in HEK293 cells, all VWF variants induced formation of WPB-like organelles that were able to recruit P-selectin, as well as FVIII. WPBs containing FVIII did not display their typical elongated shape, suggesting that FVIII affects the organization of VWF tubules therein. The finding that VWF type 2N variants are still capable of cotargeting FVIII to storage granules implies that trafficking of WPB cargo proteins does not necessarily require high-affinity assembly with VWF.


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Related Article in Blood Online:

VWF and FVIII: the origins of a great friendship
Sandra L. Haberichter
Blood 2009 113: 2873-2874. [Full Text] [PDF]





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