Viral Entry of Hepatitis B and D Viruses and Bile Salts Transportation Share Common Molecular Determinants on Sodium Taurocholate Cotransporting Polypeptide
Viral Entry of Hepatitis B and D Viruses and Bile Salts Transportation Share Common Molecular Determinants on Sodium Taurocholate Cotransporting Polypeptide
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DOI：
10.1128/jvi.03478-13
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发表时间：
2014-03-01
影响因子：
5.4
通讯作者：
Li, Wenhui
中科院分区：
文献类型：
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作者：
Yan, Huan;Peng, Bo;Li, Wenhui
肝胆汁酸转运蛋白牛磺胆酸钠共转运多肽（NTCP）负责肝细胞摄取大部分钠依赖性胆汁盐。NTCP还通过NTCP与HBV大包膜蛋白的pre-S1结构域之间的特异性相互作用作为病毒进入B型肝炎病毒（HBV）和丁型肝炎病毒（HDV）的细胞受体。然而，NTCP的这两个功能是独立的还是相互干扰的仍然是未知的。在这里，我们表明，结合前S1域的人NTCP块牛磺胆酸盐摄取的受体，相反，一些胆汁酸底物的NTCP抑制HBV和HDV进入。对胆盐结合至关重要的NTCP残基的突变严重损害HDV和HBV的病毒感染;在较小程度上，对钠结合重要的残基也抑制病毒感染。突变S267 F，对应于在约9%的东亚人群中发现的单核苷酸多态性（SNP），使得NTCP在细胞培养中没有牛磺胆酸盐转运活性或支持HBV或HDV感染的能力。这些结果表明，HBV和HDV进入的关键分子决定因素与NTCP摄取胆盐的决定因素重叠，表明病毒感染可能干扰NTCP的正常功能，胆汁酸及其衍生物具有进一步开发为抗病毒药物的潜力。
The liver bile acids transporter sodium taurocholate cotransporting polypeptide (NTCP) is responsible for the majority of sodium-dependent bile salts uptake by hepatocytes. NTCP also functions as a cellular receptor for viral entry of hepatitis B virus (HBV) and hepatitis D virus (HDV) through a specific interaction between NTCP and the pre-S1 domain of HBV large envelope protein. However, it remains unknown if these two functions of NTCP are independent or if they interfere with each other. Here we show that binding of the pre-S1 domain to human NTCP blocks taurocholate uptake by the receptor; conversely, some bile acid substrates of NTCP inhibit HBV and HDV entry. Mutations of NTCP residues critical for bile salts binding severely impair viral infection by HDV and HBV; to a lesser extent, the residues important for sodium binding also inhibit viral infection. The mutation S267F, corresponding to a single nucleotide polymorphism (SNP) found in about 9% of the East Asian population, renders NTCP without either taurocholate transporting activity or the ability to support HBV or HDV infection in cell culture. These results demonstrate that molecular determinants critical for HBV and HDV entry overlap with that for bile salts uptake by NTCP, indicating that viral infection may interfere with the normal function of NTCP, and bile acids and their derivatives hold the potential for further development into antiviral drugs.