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Homocysteine inhibits von Willebrand factor processing and secretion by
preventing transport from the endoplasmic reticulum
SR Lentz and JE Sadler
Howard Hughes Medical Institute, Department of Medicine, Jewish Hospital of
St Louis, Washington University School of Medicine, MO 63110.
Intracellular protein transport in endothelial cells is selectively
inhibited by homocysteine, a thiol amino acid associated with both
thrombosis and atherosclerosis. In a previous study, homocysteine decreased
cell surface expression of the surface transmembrane glycoprotein
thrombomodulin without decreasing secretion of another endothelial cell
protein, plasminogen activator inhibitor-1. To define further the effects
of homocysteine on protein transport, we examined the processing and
secretion of the multimeric glycoprotein von Willebrand factor (vWF) in
human umbilical vein endothelial cells. Incubation with 2 mmol/L
homocysteine resulted in complete loss of vWF multimers and prevented
asparagine-linked oligosaccharide maturation, propeptide cleavage, and
secretion; these effects are consistent with impaired exit from the
endoplasmic reticulum (ER). Dimerization was only partially inhibited,
suggesting that homocysteine causes retention of provWF in the ER without
preventing dimer formation. In pulse-chase incubations, intracellular
provWF was degraded before exiting the ER in homocysteine-treated cells.
Homocysteine also inhibited the processing and secretion of a
carboxyl-terminal truncation mutant of human provWF expressed in rat
insulinoma cells, indicating that retention in the endoplasmic reticulum
can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd
segment. These results suggest that retention of secretory proteins in the
ER is regulated by redox mechanisms and imply that the intracellular
transport of multiple endothelial cell proteins may be altered in patients
with homocystinuria.
Volume 81,
Issue 3,
pp. 683-689,
02/01/1993
Copyright © 1993 by The American Society of Hematology
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