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Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):668-679
Sialylation on O-linked glycans protects von Willebrand factor from macrophage galactose lectin-mediated clearance
Soracha E. Ward,1 Jamie M. O’Sullivan,1 Alan B. Moran,2,3 Daniel I. R. Spencer,2 Richard A. Gardner,2 Jyotika Sharma,4 Judicael Fazavana,1 Marco Monopoli,5 Thomas A. J. McKinnon,6 Alain Chion,1 Sandra Haberichter7 and
James S. O’Donnell1,8,9
1Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; 2Ludger, Ltd., Culham Science Centre, Abingdon, Oxfordshire, UK; 3Leiden University Medical Centre, Centre for Proteomics and Metabolomics, Leiden, the Netherlands; 4Department of Basic Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA; 5Department of Chemistry, Royal College of Surgeons in Ireland, Dublin, Ireland; 6Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK; 7Versiti, Blood Research Institute, Milwaukee, WI, USA; 8National Children's Research Centre, Our Lady's Children's Hospital, Dublin, Ireland and 9National Coagulation Centre, St James’s Hospital, Dublin, Ireland
ABSTRACT
Terminal sialylation determines the plasma half-life of von Willebrand factor (VWF). A role for macrophage galactose lectin (MGL) in regulating hyposialylated VWF clearance has recently been proposed. In this study, we showed that MGL influences physiolog- ical plasma VWF clearance. MGL inhibition was associated with a signifi- cantly extended mean residence time and 3-fold increase in endogenous plasma VWF antigen levels (P<0.05). Using a series of VWF truncations, we further demonstrated that the A1 domain of VWF is predominantly responsible for enabling the MGL interaction. Binding of both full-length and VWF-A1-A2-A3 to MGL was significantly enhanced in the presence of ristocetin (P<0.05), suggesting that the MGL-binding site in A1 is not fully accessible in globular VWF. Additional studies using different VWF glycoforms demonstrated that VWF O-linked glycans, clustered at either end of the A1 domain, play a key role in protecting VWF against MGL- mediated clearance. Reduced sialylation has been associated with patho- logical, increased clearance of VWF in patients with von Willebrand dis- ease. Herein, we demonstrate that specific loss of α2-3 linked sialylation from O-glycans results in markedly increased MGL-binding in vitro, and markedly enhanced MGL-mediated clearance of VWF in vivo. Our data fur- ther show that the asialoglycoprotein receptor (ASGPR) does not have a significant role in mediating the increased clearance of VWF following loss of O-sialylation. Conversely however, we observed that loss of N-linked sialylation from VWF drives enhanced circulatory clearance predominant- ly via the ASGPR. Collectively, our data support the hypothesis that in addition to regulating physiological VWF clearance, the MGL receptor works in tandem with ASGPR to modulate enhanced clearance of aber- rantly sialylated VWF in the pathogenesis of von Willebrand disease.
Introduction
von Willebrand disease (VWD) is the commonest inherited human bleeding dis- order and is caused by either quantitative or qualitative deficiency of plasma von Willebrand factor (VWF).1,2 Increased plasma clearance of VWF constitutes an important mechanism in the pathogenesis of VWD.3 The MCMDM-1VWD European study, US Zimmerman Program and Willebrand in the Netherlands (WIN) study have all found pathological, enhanced VWF clearance in approxi- mately 45% of patients with type 1 VWD, leading to the proposal that patients
Hemostasis
Correspondence:
JAMES O’DONNELL
jamesodonnell@rcsi.ie
Received: October 21, 2020. Accepted: March 12, 2021. Pre-published: March 25, 2021.
https://doi.org/10.3324/haematol.2020.274720 ©2022 Ferrata Storti Foundation
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