Faculty Collaboration Database

Intracellular trafficking of factor VIII to von Willebrand factor storage granules. J Clin Invest 1998 Feb 01;101(3):613-24

Date

03/21/1998

Pubmed ID

9449695

Pubmed Central ID

PMC508605

DOI

10.1172/JCI1250

Scopus ID

2-s2.0-0032007271 (requires institutional sign-in at Scopus site)   104 Citations

Abstract

In plasma, von Willebrand factor (vWf) associates with Factor VIII (FVIII); however, the site at which these proteins first interact has not been defined. Administration of 1-desamino-8-D-arginine vasopressin (DDAVP) causes a rapid, concomitant elevation in plasma levels of both vWf and FVIII, suggesting the existence of a DDAVP-releasable storage pool for both proteins. To determine whether vWf and FVIII can associate intracellularly and colocalize to storage vesicles, we transfected AtT-20 cells with vWf and FVIII expression plasmids. FVIII alone was not detectable within storage granules; however, transfection of vWf cDNA into the same cell caused FVIII to alter its intracellular trafficking and to undergo granular storage, colocalizing to the vWf-containing granules. In contrast, colocalization of FVIII was not observed when these cells were transfected with plasmids encoding defective FVIII-binding vWf mutants. Transfection of bovine endothelial cells with FVIII further demonstrated vesicular storage of FVIII with vWf in Weibel-Palade bodies. Since gene therapy of hemophilia A may ultimately target endothelium or hematopoietic stem cells, the interaction between vWf and FVIII within a secretory cell is important. Thus, vWf can alter the intracellular trafficking of FVIII from a constitutive to a regulated secretory pathway, thereby producing an intracellular storage pool of both proteins.

Author List

Rosenberg JB, Foster PA, Kaufman RJ, Vokac EA, Moussalli M, Kroner PA, Montgomery RR

Author

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CHO Cells
COS Cells
Cattle
Cells, Cultured
Cricetinae
Endothelium, Vascular
Factor VIII
Fluorescent Antibody Technique, Indirect
Humans
Intracellular Fluid
Mice
Molecular Chaperones
Protein Processing, Post-Translational
Tumor Cells, Cultured
von Willebrand Factor