Sialylation on O-linked glycans protects von Willebrand factor from macrophage galactose lectin-mediated clearance.
Sialylation on O-linked glycans protects von Willebrand factor from macrophage galactose lectin-mediated clearance.
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DOI：
10.3324/haematol.2020.274720
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发表时间：
2022-03-01
期刊：
影响因子：
10.1
通讯作者：
O'Donnell JS
中科院分区：
文献类型：
--
作者：
Ward SE;O'Sullivan JM;Moran AB;Spencer DIR;Gardner RA;Sharma J;Fazavana J;Monopoli M;McKinnon TAJ;Chion A;Haberichter S;O'Donnell JS
末端唾液酸化决定了血管性血友病因子（VWF）的血浆半衰期。巨噬细胞半乳糖凝集素（MGL）的作用，在调节hyposialylated VWF清除最近提出。在这项研究中，我们表明，MGL影响生理血浆VWF清除。MGL抑制与显著延长的平均停留时间和内源性血浆VWF抗原水平增加3倍相关（P<0.05）。使用一系列的VWF截短，我们进一步证明，A1域的VWF是主要负责使MGL的相互作用。在利托那肽存在下，全长和VWF-A1-A2-A3与MGL的结合均显著增强（P<0.05），表明A1中的MGL结合位点在球状VWF中不完全可及。使用不同VWF糖型的其他研究表明，聚集在A1结构域两端的VWF O-连接聚糖在保护VWF免受MGL介导的清除中起关键作用。在血管性血友病患者中，唾液酸化减少与病理性VWF清除增加相关。在此，我们证明了O-聚糖α2-3连接的唾液酸化的特异性丧失导致体外MGL结合显著增加，并显著增强体内MGL介导的VWF清除。我们的数据进一步表明，去唾液酸糖蛋白受体（ASGPR）在介导O-唾液酸化丧失后VWF清除率增加方面没有显著作用。然而，相反地，我们观察到VWF的N-连接唾液酸化的丧失主要通过ASGPR驱动增强的循环清除。总的来说，我们的数据支持这样的假设，即除了调节生理VWF清除，MGL受体协同ASGPR调节异常唾液酸化VWF在血管性血友病发病机制中的清除增强。
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 physiological plasma VWF clearance. MGL inhibition was associated with a significantly 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 MGLmediated clearance. Reduced sialylation has been associated with pathological, increased clearance of VWF in patients with von Willebrand disease. 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 further 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 predominantly 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 aberrantly sialylated VWF in the pathogenesis of von Willebrand disease.
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