Hepatitis C Virus Particle Assembly Involves Phosphorylation of NS5A by the c-Abl Tyrosine Kinase |
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Authors: | Shota Yamauchi Kenji Takeuchi Kazuyasu Chihara Xuedong Sun Chisato Honjoh Hatsumi Yoshiki Hak Hotta Kiyonao Sada |
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Institution: | From the ‡Division of Genome Science and Microbiology, Department of Pathological Sciences, Faculty of Medical Sciences.;the ¶Third Department of Internal Medicine, Faculty of Medical Sciences, and ;the §Organization for Life Science Advancement Programs, University of Fukui, Fukui 910-1193, Japan and ;the ‖Division of Microbiology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan |
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Abstract: | Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is thought to regulate the replication of viral RNA and the assembly of virus particles in a serine/threonine phosphorylation-dependent manner. However, the host kinases that phosphorylate NS5A have not been fully identified. Here, we show that HCV particle assembly involves the phosphorylation of NS5A by the c-Abl tyrosine kinase. Pharmacological inhibition or knockdown of c-Abl reduces the production of infectious HCV (J6/JFH1) particles in Huh-7.5 cells without markedly affecting viral RNA translation and replication. NS5A is tyrosine-phosphorylated in HCV-infected cells, and this phosphorylation is also reduced by the knockdown of c-Abl. Mutational analysis reveals that NS5A tyrosine phosphorylation is dependent, at least in part, on Tyr330 (Tyr2306 in polyprotein numbering). Mutation of this residue to phenylalanine reduces the production of infectious HCV particles but does not affect the replication of the JFH1 subgenomic replicon. These findings suggest that c-Abl promotes HCV particle assembly by phosphorylating NS5A at Tyr330. |
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Keywords: | ABL tyrosine kinase hepatitis C virus (HCV) host-pathogen interaction virology virus assembly |
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