Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum

S R Lentz; J E Sadler

doi:10.1182/blood.V81.3.683.683

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Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum

Journal article

Open access

Peer reviewed

Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum

S R Lentz and J E Sadler

Blood, Vol.81(3), pp.683-689

02/01/1993

DOI: 10.1182/blood.V81.3.683.683

PMID: 8427960

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Abstract

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.

Electrophoresis, Polyacrylamide Gel

Humans

von Willebrand Factor - isolation & purification

Cells, Cultured

Endoplasmic Reticulum - metabolism

Umbilical Veins

Endothelium, Vascular - drug effects

Sulfur Radioisotopes

von Willebrand Factor - biosynthesis

Macromolecular Substances

Autoradiography

Protein Processing, Post-Translational - drug effects

Endothelium, Vascular - metabolism

Endoplasmic Reticulum - drug effects

Homocysteine - pharmacology

Biological Transport - drug effects

Cysteine - metabolism

Kinetics

von Willebrand Factor - metabolism

Details

Title: Subtitle: Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum
Creators: S R Lentz - Howard Hughes Medical Institute, Department of Medicine, Jewish Hospital of St Louis, Washington University School of Medicine, MO 63110
J E Sadler
Resource Type: Journal article
Publication Details: Blood, Vol.81(3), pp.683-689
DOI: 10.1182/blood.V81.3.683.683
PMID: 8427960
NLM abbreviation: Blood
ISSN: 0006-4971
eISSN: 1528-0020
Grant note: T32 HLBI 07088 / NHLBI NIH HHS HLBI 14147 / NHLBI NIH HHS
Language: English
Date published: 02/01/1993
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094654902771

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