Hepatitis C Virus Induces Epidermal Growth Factor Receptor Activation via CD81 Binding for Viral Internalization and Entry
Hepatitis C Virus Induces Epidermal Growth Factor Receptor Activation via CD81 Binding for Viral Internalization and Entry
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DOI：
10.1128/jvi.00750-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Kapadia, Sharookh B.
中科院分区：
文献类型：
--
作者：
Diao, Jingyu;Pantua, Homer;Kapadia, Sharookh B.
虽然表皮生长因子受体（EGFR）已被证明是重要的多种病毒，包括丙型肝炎病毒（HCV）的进入过程中，EGFR促进HCV进入的分子机制还没有得到很好的理解。使用感染性细胞培养HCV模型（HCCLN），我们证明HCCLN颗粒与人肝细胞的结合诱导EGFR活化，这依赖于HCV和CD81之间的相互作用，而不是紧密连接蛋白1。EGFR活化也可以通过抗体介导的CD81交联来诱导。此外，增强HCV进入动力学的EGFR配体诱导EGFR内化和与CD81共定位。虽然EGFR激酶抑制剂主要通过阻止EGFR内吞作用来抑制HCV感染，但阻断EGFR配体结合的抗体或EGFR下游信号传导抑制剂对HCV进入没有影响。这些数据表明，EGFR内化是HCV进入的关键，并确定了迄今未知的CD81和EGFR之间的关联。
While epidermal growth factor receptor (EGFR) has been shown to be important in the entry process for multiple viruses, including hepatitis C virus (HCV), the molecular mechanisms by which EGFR facilitates HCV entry are not well understood. Using the infectious cell culture HCV model (HCVcc), we demonstrate that the binding of HCVcc particles to human hepatocyte cells induces EGFR activation that is dependent on interactions between HCV and CD81 but not claudin 1. EGFR activation can also be induced by antibody mediated cross-linking of CD81. In addition, EGFR ligands that enhance the kinetics of HCV entry induce EGFR internalization and colocalization with CD81. While EGFR kinase inhibitors inhibit HCV infection primarily by preventing EGFR endocytosis, antibodies that block EGFR ligand binding or inhibitors of EGFR downstream signaling have no effect on HCV entry. These data demonstrate that EGFR internalization is critical for HCV entry and identify a hitherto-unknown association between CD81 and EGFR.