Specific interaction of the envelope glycoproteins E1 and E2 with liver heparan sulfate involved in the tissue tropismatic infection by hepatitis C virus
Specific interaction of the envelope glycoproteins E1 and E2 with liver heparan sulfate involved in the tissue tropismatic infection by hepatitis C virus
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DOI：
10.1007/s10719-012-9388-z
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发表时间：
2012-05-01
影响因子：
3
通讯作者：
Sugahara, Kazuyuki
中科院分区：
文献类型：
--
作者：
Kobayashi, Fumi;Yamada, Shuhei;Sugahara, Kazuyuki
丙型肝炎病毒感染过程的第一步是与宿主细胞的附着，这被认为是通过包膜糖蛋白E1和E2与细胞表面的糖胺聚糖相互作用而介导的。本研究利用多种糖胺多聚糖、不同牛组织中的硫酸肝素(HS)以及牛肝中的硫酸软骨素(CS)和皮肤素硫酸盐，研究了它们与重组E1和E2蛋白的直接相互作用。有趣的是，在来自不同牛组织的HS制剂中，只有肝脏HS与E1和E2强烈结合。由于来自肝脏的HS是丙型肝炎病毒的靶组织，与来自其他组织的HS相比，具有高度的硫酸盐化结构，因此本研究结果表明，肝细胞表面的HS-蛋白多糖似乎是定义丙型肝炎病毒感染的肝脏特异性组织嗜性的分子之一。与化学修饰的肝素衍生物的相互作用分析表明，病毒蛋白与肝素/HS的结合不仅是由简单的离子相互作用介导的，而且6-O-硫化和N-硫化是重要的。需要等于或大于10聚体的肝素低聚糖来抑制结合。值得注意的是，从鱿鱼软骨中提取的高度硫酸盐化的CS-E制剂也与两种病毒蛋白强烈相互作用，并抑制假型丙型肝炎病毒进入靶细胞，这表明高度硫酸盐化的CS-E可能是有用的抗丙型肝炎病毒药物。
The first step in the process of infections by the hepatitis C virus (HCV) is attachment to the host cell, which is assumed to be mediated by interaction of the envelope glycoproteins E1 and E2 with cell surface glycosaminoglycans. In this study, a variety of glycosaminoglycans, heparan sulfate (HS) from various bovine tissues as well as chondroitin sulfate (CS)/dermatan sulfate from bovine liver, were used to examine the direct interaction with recombinant E1 and E2 proteins. Intriguingly, among HS preparations from various bovine tissues, only liver HS strongly bound to both E1 and E2. Since HS from liver, which is the target tissue of HCV, contains highly sulfated structures compared to HS from other tissues, the present results suggest that HS-proteoglycan on the liver cell surface appears to be one of the molecules that define the liver-specific tissue tropism of HCV infection. The interaction assay with chemically modified heparin derivatives provided evidence that the binding of the viral proteins to heparin/HS is not only mediated by simple ionic interactions, but that the 6-O-sulfation and N-sulfation are important. Heparin oligosaccharides equal to or larger than 10-mer were required to inhibit the binding. Notably, a highly sulfated CS-E preparation from squid cartilage also strongly interacted with both viral proteins and inhibited the entry of pseudotype HCV into the target cells, suggesting that the highly sulfated CS-E might be useful as an anti-HCV drug.