Hepatitis C Virus Induces CD81 and Claudin-1 Endocytosis
Hepatitis C Virus Induces CD81 and Claudin-1 Endocytosis
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DOI：
10.1128/jvi.06996-11
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发表时间：
2012-04-01
影响因子：
5.4
通讯作者：
McKeating, Jane A.
中科院分区：
文献类型：
--
作者：
Farquhar, Michelle J.;Hu, Ke;McKeating, Jane A.
丙型肝炎病毒（HCV）导致进行性肝病和肝细胞癌。目前的治疗方法仅部分有效，需要针对病毒和宿主途径的新疗法。病毒进入宿主细胞为治疗干预提供了一个保守的靶点。四跨蛋白CD81，清道夫受体B类成员I，紧密连接蛋白claudin-1和occludin已被确定为必需的进入受体。关于受体贩运在HCV入境中的作用的信息有限。我们在这里证明了抗CD81抗体在病毒内化后抑制HCV感染的后期，这表明细胞内CD81在HCV感染中的作用。据报道，一些四跨蛋白通过其c端细胞质结构域的基序内化；然而，CD81缺乏这样的基序，导致一些实验室提出CD81内吞作用在HCV进入中的作用有限。我们证明了CD81的内在化是通过网格蛋白和动力蛋白依赖的过程，独立于其细胞质结构域，这表明了相关伴侣蛋白在调节CD81运输中的作用。活细胞成像显示CD81和claudin-1与表达Rab5的核内体共吞并融合，支持该受体复合物在HCV内化中的作用。受体特异性抗体和HCV颗粒增加CD81和claudin-1内吞作用，支持HCV刺激受体运输促进颗粒内化的模型。
Hepatitis C virus (HCV) leads to progressive liver disease and hepatocellular carcinoma. Current treatments are only partially effective, and new therapies targeting viral and host pathways are required. Virus entry into a host cell provides a conserved target for therapeutic intervention. Tetraspanin CD81, scavenger receptor class B member I, and the tight-junction proteins claudin-1 and occludin have been identified as essential entry receptors. Limited information is available on the role of receptor trafficking in HCV entry. We demonstrate here that anti-CD81 antibodies inhibit HCV infection at late times after virus internalization, suggesting a role for intracellular CD81 in HCV infection. Several tetraspanins have been reported to internalize via motifs in their C-terminal cytoplasmic domains; however, CD81 lacks such motifs, leading several laboratories to suggest a limited role for CD81 endocytosis in HCV entry. We demonstrate CD81 internalization via a clathrin- and dynamin-dependent process, independent of its cytoplasmic domain, suggesting a role for associated partner proteins in regulating CD81 trafficking. Live cell imaging demonstrates CD81 and claudin-1 coendocytosis and fusion with Rab5 expressing endosomes, supporting a role for this receptor complex in HCV internalization. Receptor-specific antibodies and HCV particles increase CD81 and claudin-1 endocytosis, supporting a model wherein HCV stimulates receptor trafficking to promote particle internalization.