Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate
Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate
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DOI：
10.1074/jbc.m302267200
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发表时间：
2003-10-17
影响因子：
4.8
通讯作者：
Baumert, TF
中科院分区：
文献类型：
--
作者：
Barth, H;Schäfer, C;Baumert, TF
丙型肝炎病毒（HCV）包膜糖蛋白E2的N端带正电荷的残基的保守性表明病毒包膜与细胞表面糖胺聚糖的相互作用。使用重组包膜糖蛋白E2和病毒样颗粒作为细胞结合的配体，我们证明了细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）在介导HCV包膜-靶细胞相互作用中起重要作用。肝素和肝源性高度硫酸化硫酸乙酰肝素（而非其他可溶性糖胺聚糖）以剂量依赖性方式抑制细胞结合和病毒样颗粒进入。通过用肝素酶预处理降解细胞表面硫酸乙酰肝素导致病毒包膜蛋白结合的显著减少。表面等离子体共振分析表明E2与肝素（高度硫酸化硫酸乙酰肝素的结构同系物）具有高亲和力相互作用（K-D 5.2 x 10（-9）M）。E2高变区-1的缺失减少了E2-肝素的相互作用，这表明N-末端E2区域中的带正电荷的残基在介导E2-HSPG结合中起重要作用。总之，我们的研究结果首次表明，HCV包膜的细胞结合需要E2-HSPG相互作用。E2与细胞HSPG的对接可能是HCV与细胞表面相互作用的初始步骤，导致受体介导的进入并引发感染。
The conservation of positively charged residues in the N terminus of the hepatitis C virus (HCV) envelope glycoprotein E2 suggests an interaction of the viral envelope with cell surface glycosaminoglycans. Using recombinant envelope glycoprotein E2 and virus-like particles as ligands for cellular binding, we demonstrate that cell surface heparan sulfate proteoglycans ( HSPG) play an important role in mediating HCV envelope-target cell interaction. Heparin and liver-derived highly sulfated heparan sulfate but not other soluble glycosaminoglycans inhibited cellular binding and entry of virus-like particles in a dose-dependent manner. Degradation of cell surface heparan sulfate by pretreatment with heparinases resulted in a marked reduction of viral envelope protein binding. Surface plasmon resonance analysis demonstrated a high affinity interaction ( K-D 5.2 x 10(-9) M) of E2 with heparin, a structural homologue of highly sulfated heparan sulfate. Deletion of E2 hypervariable region-1 reduced E2-heparin interaction suggesting that positively charged residues in the N-terminal E2 region play an important role in mediating E2-HSPG binding. In conclusion, our results demonstrate for the first time that cellular binding of HCV envelope requires E2-HSPG interaction. Docking of E2 to cellular HSPG may be the initial step in the interaction between HCV and the cell surface resulting in receptor-mediated entry and initiation of infection.