Forms a heterodimer with envelope glycoprotein E1, which mediates virus attachment to the host cell, virion internalization through clathrin-dependent endocytosis and fusion with host membrane. Fusion with the host cell is most likely mediated by both E1 and E2, through conformational rearrangements of the heterodimer required for fusion rather than a classical class II fusion mechanism. The interaction between envelope glycoprotein E2 and host apolipoprotein E/APOE allows the proper assembly, maturation and infectivity of the viral particles. This interaction is probably promoted via the up-regulation of cellular autophagy by the virus. E1/E2 heterodimer binds host apolipoproteins such as APOB and APOE thereby forming a lipo-viro-particle (LVP). APOE associated to the LVP allows the initial virus attachment to cell surface receptors such as the heparan sulfate proteoglycans (HSPGs), syndecan-1 (SDC1), syndecan-1 (SDC2), the low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SCARB1). The cholesterol transfer activity of SCARB1 allows E2 exposure and binding of E2 to SCARB1 and the tetraspanin CD81. E1/E2 heterodimer binding on CD81 activates the epithelial growth factor receptor (EGFR) signaling pathway. Diffusion of the complex E1-E2-EGFR-SCARB1-CD81 to the cell lateral membrane allows further interaction with Claudin 1 (CLDN1) and occludin (OCLN) to finally trigger HCV entry. Inhibits host EIF2AK2/PKR activation, preventing the establishment of an antiviral state. Viral ligand for CD209/DC-SIGN and CLEC4M/DC-SIGNR, which are respectively found on dendritic cells (DCs), and on liver sinusoidal endothelial cells and macrophage-like cells of lymph node sinuses. These interactions allow the capture of circulating HCV particles by these cells and subsequent facilitated transmission to permissive cells such as hepatocytes and lymphocyte subpopulations. The interaction between E2 and host amino acid transporter complex formed by SLC3A2 and SLC7A5/LAT1 may facilitate viral entry into host cell 