Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands

Ellies, Lesley G.; Ditto, David; Lévy, Gallia; Wahrenbrock, Mark G.; Ginsburg, David; Varki, Ajit; Le, Dzung; Marth, Jamey D.

doi:10.1073/pnas.142005099

Cited by 172 publications

(191 citation statements)

References 45 publications

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“…treatment with either AUS NA (5 U/kg) or PBS. Plasma was isolated for measurements of the abundance or activity of specific blood coagulation factors, as previously described (24,25). Measurements of glycoprotein abundance were obtained with anti-factor antibodies.…”

Section: Discussionmentioning

confidence: 99%

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Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

Grewal

Aziz

Uchiyama

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.

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Section: Discussionmentioning

confidence: 99%

“…treatment with either AUS NA (5 U/kg) or PBS. Ratios of exposed galactose per unit of protein antigen were calculated as indicated and as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

Grewal

Aziz

Uchiyama

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…One of the very few parameters that has been reported to date to influence VWF clearance is the VWF glycosylation profile (12,(21)(22)(23)(24). For instance, by using an animal model it has been shown that, in the absence of the enzyme ST3Gal-IV, the half-life of endogenous VWF is reduced 2-fold (24).…”

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confidence: 99%

“…For instance, by using an animal model it has been shown that, in the absence of the enzyme ST3Gal-IV, the half-life of endogenous VWF is reduced 2-fold (24). Moreover, in a patient group referred to the hospital for real or suspected bleeding disorder, reduced ST3Gal-IV-mediated sialylation was observed to be associated with reduced VWF plasma levels (24).…”

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confidence: 99%

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Lenting

Westein

Terraube

et al. 2004

Journal of Biological Chemistry

135

189

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To explore the molecular basis of von Willebrand factor (VWF) clearance, an experimental model employing VWF-deficient mice was developed. Biodistribution was examined by the injection of radiolabeled VWF, which was primarily directed to the liver with minor amounts in other organs. Disappearance of VWF from plasma was characterized by a rapid initial phase (t1 ⁄2 ␣ ‫؍‬ 13 min) and a slow secondary phase (t1 ⁄2 ␤ ‫؍‬ 3 h), with a mean residence time (MRT) of 2.8 h. A similar clearance was observed for VWF consisting of only high or low molecular weight multimers, indicating that, in our experimental model, clearance is independent of multimeric distribution. This allowed us to compare the survival of fulllength VWF to truncated variants. Deletion of both the amino-terminal D -D3 and carboxyl-terminal D4-CK domains resulted in a fragment with a similar clearance to wild-type VWF. Deletion of only the D -D3 region was associated with an almost 2-fold lower recovery and increased clearance (MRT ‫؍‬ 1.6 h), whereas deletion of only the D4-CK region resulted in a significantly reduced clearance (MRT ‫؍‬ 4.5 h, p < 0.02). These results point to a role of the D -D3 region in preventing clearance of VWF. Furthermore, replacement of D3 domain residue Arg-1205 by His resulted in a markedly increased clearance (MRT ‫؍‬ 0.3 h; p ‫؍‬ 0.004). Therefore, this mutation seems to abrogate the protective effect of the D -D3 region. In vitro analysis of this mutant also revealed a 2-fold reduced affinity for VWF propeptide at low pH, showing that mutation of Arg-1205 results not only in an increased clearance rate but is also associated with an impaired pH-dependent interaction with VWF propeptide.von Willebrand factor (VWF) 1 is a multimeric plasma protein that participates in the hemostatic process. The absence of functional VWF is associated with an abnormal bleeding tendency known as von Willebrand Disease (VWD) (1, 2). VWF contributes to hemostasis in a dual manner. First, it promotes the adhesion of platelets at sites of vascular injury by acting as a molecular bridge between the sub-endothelial collagen matrix and the platelet-surface receptor complex glycoprotein (Gp) Ib␣/IX/V (3). In addition, VWF serves as a carrier protein for coagulation factor VIII (FVIII) in the circulation. This chaperone function results in stabilization of the FVIII heterodimeric structure (4) and protection of FVIII from premature clearance by the low density lipoprotein receptor-related protein (5, 6).VWF is produced and stored in endothelial cells and megakaryocytes. It is synthesized as pre-pro-VWF, a single chain polypeptide with the domain structure

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“…The addition of Sia is catalyzed by a family of 20 sialyltransferase enzymes, which transfer Sia via 2-3, 2-6 and 2-8 linkages to various glycan acceptors [46]. The disruption of sialyltransferase genes in mice often results in immune and hematologic phenotypes [47][48][49]. Very recently, mutations in the 2-3 sialyltransferase gene ST3GAL3 (OMIM ID: 606494) have been associated with nonsyndromic mental retardation [50].…”

Section: 2-3 Sia-transferase IIImentioning

confidence: 99%

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

116

103

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands

Cited by 172 publications

References 45 publications

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

Diseases of glycosylation beyond classical congenital disorders of glycosylation

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