Abstract
Abl is a central regulator of multiple cellular processes controlling actin dynamics, proliferation, and differentiation. Here, we showed that knockdown of Abl impaired hepatitis C virus (HCV) propagation. Treatment of Abl tyrosine kinase-specific inhibitor, imatinib and dasatinib, also significantly decreased HCV RNA and protein levels in HCV-infected cells. We showed that both imatinib and dasatinib selectively inhibited HCV infection at the entry step of HCV life cycle, suggesting that Abl kinase activity may be necessary for HCV entry. Using HCV pseudoparticle infection assays, we verified that Abl is required for viral entry. By employing transferrin uptake and immunofluorescence assays, we further demonstrated that Abl was involved in HCV entry at a clathrin-mediated endocytosis step. These data suggest that Abl may represent a novel host factor for HCV entry.
Highlights
Hepatitis C virus causes both acute and persistent infections and often leads to liver cirrhosis and hepatocellular carcinoma (Saito et al, 1990)
We further showed that Abl tyrosine kinase-specific inhibitors, imatinib and dasatinib, selectively inhibited the entry step of the hepatitis C virus (HCV) life cycle
To demonstrate whether Abl kinase activity was required for HCV propagation, Huh7.5 cells treated with imatinib were either mock-infected or infected with Jc1 and total cell lysates were immunoblotted with the indicated antibodies
Summary
Hepatitis C virus causes both acute and persistent infections and often leads to liver cirrhosis and hepatocellular carcinoma (Saito et al, 1990). HCV genome consists of 9,600 nucleotides and encodes a single polyprotein precursor of more than 3,000 amino acids This polyprotein is processed cotranslationally and post-translationally by viral and host cellular proteases into 10 functional proteins, including three structural (core, E1, and E2), the p7 viroporin, and the six non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (Lindenbach and Rice, 2005). We further showed that Abl tyrosine kinase-specific inhibitors, imatinib and dasatinib, selectively inhibited the entry step of the HCV life cycle. We showed that Abl was involved in clathrin-mediated endocytosis These data suggest that Abl is a host factor required for HCV entry, and thereby it may be a potential target for the treatment of HCV infection
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