Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA.
Department of Microbiology, The University of Chicago, Chicago, IL 60637, USA.
Cell Host Microbe. 2018 Mar 14;23(3):382-394.e5. doi: 10.1016/j.chom.2018.02.005.
Hepatitis C virus (HCV) enters hepatocytes via various entry factors, including scavenger receptor BI (SR-B1), cluster of differentiation 81 (CD81), epidermal growth factor receptor (EGFR), claudin-1 (CLDN1), and occludin (OCLN). As CLDN1 and OCLN are not readily accessible due to their tight junctional localization, HCV likely accesses them by either disrupting cellular polarity or migrating to the tight junction. In this study, we image HCV entry into a three-dimensional polarized hepatoma system and reveal that the virus sequentially engages these entry factors through actin-dependent mechanisms. HCV initially localizes with the early entry factors SR-B1, CD81, and EGFR at the basolateral membrane and then accumulates at the tight junction in an actin-dependent manner. HCV associates with CLDN1 and then OCLN at the tight junction and is internalized via clathrin-mediated endocytosis by an active process requiring EGFR. Thus, HCV uses a dynamic and multi-step process to engage and enter host cells.
丙型肝炎病毒（HCV）通过多种进入因子进入肝细胞，包括清道夫受体 BI（SR-B1）、分化群 81（CD81）、表皮生长因子受体（EGFR）、紧密连接蛋白 1（CLDN1）和封闭蛋白（OCLN）。由于 CLDN1 和 OCLN 由于其紧密连接的定位而不易接近，因此 HCV 可能通过破坏细胞极性或迁移到紧密连接处来接近它们。在这项研究中，我们对 HCV 进入三维极化肝癌系统的过程进行了成像，并揭示了该病毒通过肌动蛋白依赖性机制依次与这些进入因子结合。HCV 最初与早期进入因子 SR-B1、CD81 和 EGFR 在基底外侧膜处定位，然后以肌动蛋白依赖性方式在紧密连接处积累。HCV 与紧密连接上的 CLDN1 结合，然后与 OCLN 结合，并通过网格蛋白介导的内吞作用被内化，这是一个需要 EGFR 的主动过程。因此，HCV 使用动态的多步骤过程来结合和进入宿主细胞。
