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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957944/
J Virol. 2014 Mar; 88(6): 3273–3284.
doi: 10.1128/JVI.03478-13
PMCID: PMC3957944
PMID: 24390325
Viral Entry of Hepatitis B and D Viruses and Bile Salts Transportation Share Common Molecular Determinants on Sodium Taurocholate Cotransporting Polypeptide
Huan Yan,a Bo Peng,a Yang Liu,a Guangwei Xu,a,b Wenhui He,a,b Bijie Ren,a Zhiyi Jing,a Jianhua Sui,a and Wenhui Licorresponding authora
G. McFadden, Editor
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ABSTRACT
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.
IMPORTANCE Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), are important human pathogens. Available therapeutics against HBV are limited, and there is no drug that is clinically available for HDV infection. A liver bile acids transporter (sodium taurocholate cotransporting polypeptide [NTCP]) critical for maintaining homeostasis of bile acids serves as a functional receptor for HBV and HDV. We report here that the NTCP-binding lipopeptide that originates from the first 47 amino acids of the pre-S1 domain of the HBV L protein blocks taurocholate transport. Some bile salts dose dependently inhibit HBV and HDV infection mediated by NTCP; molecular determinants of NTCP critical for HBV and HDV entry overlap with that for bile acids transport. This work advances our understanding of NTCP-mediated HBV and HDV infection in relation to NTCP's physiological function. Our results also suggest that bile acids or their derivatives hold potential for development into novel drugs against HBV and HDV infection.
J Virol。 2014年3月； 88（6）：3273-3284。
doi：10.1128 / JVI.03478-13
PMCID：PMC3957944
PMID：24390325
乙型和丁型肝炎病毒的病毒进入和胆汁盐运输在牛磺胆酸钠共转运多肽上具有共同的分子决定因素
颜欢，博鹏，刘洋，徐光伟，a，b何文慧，a，b毕洁杰，a智一，隋建华，a和文慧通讯作者
G. McFadden，编辑
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肝胆汁酸转运蛋白牛磺胆酸钠共转运多肽（NTCP）负责肝细胞对钠依赖性胆汁盐的摄取。 NTCP还通过NTCP与HBV大包膜蛋白的S1前结构域之间的特异性相互作用，充当乙型肝炎病毒（HBV）和D型肝炎病毒（HDV）病毒进入的细胞受体。但是，仍然不清楚NTCP的这两个功能是相互独立的还是相互干扰。在这里，我们显示前S1域与人NTCP的结合可阻止牛磺胆酸盐被受体摄取；相反，NTCP的某些胆汁酸底物可抑制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了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S267F对应于约9％的东亚人口中发现的单核苷酸多态性（SNP），使NTCP在细胞培养中既没有牛磺胆酸盐转运活性也没有支持HBV或HDV感染的能力。这些结果表明，对于HBV和HDV进入至关重要的分子决定簇与NTCP摄取胆汁盐的分子决定簇重叠，表明病毒感染可能会干扰NTCP的正常功能，胆汁酸及其衍生物具有进一步开发抗病毒药物的潜力。
重要信息人类乙型肝炎病毒（HBV）及其附属病毒D型肝炎病毒（HDV）是重要的人类病原体。可用的抗HBV疗法有限，而且尚无临床上可用于HDV感染的药物。对维持胆汁酸的稳态至关重要的肝胆汁酸转运蛋白（牛磺胆酸钠共转运多肽[NTCP]）是HBV和HDV的功能性受体。我们在这里报告，NTCP结合脂肽起源于HBV L蛋白的pre-S1域的前47个氨基酸，阻断牛磺胆酸盐的转运。一些胆汁盐剂量依赖性地抑制由NTCP介导的HBV和HDV感染。 HBV和HDV进入至关重要的NTCP分子决定因素与胆汁酸运输的分子决定因素重叠。这项工作使我们对与NTCP的生理功能有关的NTCP介导的HBV和HDV感染有了更深入的了解。我们的研究结果还表明，胆汁酸或其衍生物具有发展成为抗HBV和HDV感染新药的潜力。 |
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发表于 2020-11-22 15:51
