The matrix metalloproteinase ADAM10 supports hepatitis C virus entry and cell-to-cell spread via its sheddase activity

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. The epidermal growth factor receptor (EGFR) family members are host factors for several viruses including hepatitis C virus (HCV). In the context of HCV infection, EGFR activation and internalization is critical for HCV entry. A known mechanism of transactivation of EGFR family receptors via EGF or E-cadherin shedding involves the disintegrin and matrix metalloproteinase 10 (ADAM10). In this study, we use pharmacological inhibition, siRNA-mediated silencing, genetic ablation of ADAM10 and complementation with the EGFR family member substrates EGF and E-cadherin to show that ADAM10 supports HCV entry and cell-to-cell spread via EGFR family member transactivation.

Automated summary

This study reveals the critical role of ADAM10 as a host factor for HCV, supporting HCV entry and cell-to-cell spread through EGFR family member transactivation.