Hepatitis C virus (HCV) exploits the four entry factors CD81, scavenger receptor class B type I (SR-BI, also known as SCARB1), occludin, and claudin-1 as well as the co-factor epidermal growth factor receptor (EGFR) to infect human hepatocytes. Here, we report that the disintegrin and matrix metalloproteinase 10 (ADAM10) associates with CD81, SR-BI, and EGFR and acts as HCV host factor. Pharmacological inhibition, siRNA-mediated silencing and genetic ablation of ADAM10 reduced HCV infection. ADAM10 was dispensable for HCV replication but supported HCV entry and cell-to-cell spread. Substrates of the ADAM10 sheddase including epidermal growth factor (EGF) and E-cadherin, which activate EGFR family members, rescued HCV infection of ADAM10 knockout cells. ADAM10 did not influence infection with other enveloped RNA viruses such as alphaviruses and a common cold coronavirus. Collectively, our study reveals a critical role for the sheddase ADAM10 as a HCV host factor, contributing to EGFR family member transactivation and as a consequence to HCV uptake.

中文翻译：

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基质金属蛋白酶 ADAM10 通过其脱落酶活性支持丙型肝炎病毒进入和细胞间传播。

丙型肝炎病毒 (HCV) 利用四种进入因子 CD81、B 型 I 型清道夫受体 (SR-BI，也称为 SCARB1)、occludin 和 claudin-1 以及辅助因子表皮生长因子受体 (EGFR)感染人类肝细胞。在这里，我们报告解整合素和基质金属蛋白酶 10 (ADAM10) 与 CD81、SR-BI 和 EGFR 相关，并充当 HCV 宿主因子。ADAM10 的药理抑制、siRNA 介导的沉默和基因消除可减少 HCV 感染。ADAM10 对于 HCV 复制不是必需的，但支持 HCV 进入和细胞间传播。ADAM10 脱落酶的底物包括表皮生长因子 (EGF) 和 E-钙粘蛋白，可激活 EGFR 家族成员，挽救 ADAM10 敲除细胞的 HCV 感染。ADAM10 不影响其他有包膜 RNA 病毒（如甲病毒和普通感冒冠状病毒）的感染。总的来说，我们的研究揭示了脱落酶 ADAM10 作为 HCV 宿主因子的关键作用，有助于 EGFR 家族成员反式激活并导致 HCV 摄取。