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Journal of Virology, August 2008, p. 7964-7976, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00826-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Interaction of Hepatitis C Virus Nonstructural Protein 5A with Core Protein Is Critical for the Production of Infectious Virus Particles {triangledown}

Takahiro Masaki,1 Ryosuke Suzuki,1 Kyoko Murakami,1 Hideki Aizaki,1 Koji Ishii,1 Asako Murayama,1 Tomoko Date,1 Yoshiharu Matsuura,2 Tatsuo Miyamura,1 Takaji Wakita,1 and Tetsuro Suzuki1*

Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan,1 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita-shi, Osaka 565-0871, Japan2

Received 17 April 2008/ Accepted 22 May 2008

Nonstructural protein 5A (NS5A) of the hepatitis C virus (HCV) possesses multiple and diverse functions in RNA replication, interferon resistance, and viral pathogenesis. Recent studies suggest that NS5A is involved in the assembly and maturation of infectious viral particles; however, precisely how NS5A participates in virus production has not been fully elucidated. In the present study, we demonstrate that NS5A is a prerequisite for HCV particle production as a result of its interaction with the viral capsid protein (core protein). The efficiency of virus production correlated well with the levels of interaction between NS5A and the core protein. Alanine substitutions for the C-terminal serine cluster in domain III of NS5A (amino acids 2428, 2430, and 2433) impaired NS5A basal phosphorylation, leading to a marked decrease in NS5A-core interaction, disturbance of the subcellular localization of NS5A, and disruption of virion production. Replacing the same serine cluster with glutamic acid, which mimics the presence of phosphoserines, partially preserved the NS5A-core interaction and virion production, suggesting that phosphorylation of these serine residues is important for virion production. In addition, we found that the alanine substitutions in the serine cluster suppressed the association of the core protein with viral genome RNA, possibly resulting in the inhibition of nucleocapsid assembly. These results suggest that NS5A plays a key role in regulating the early phase of HCV particle formation by interacting with core protein and that its C-terminal serine cluster is a determinant of the NS5A-core interaction.

* Corresponding author. Mailing address: Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan. Phone: 81 3 5285 1111. Fax: 81 3 5285 1161. E-mail: tesuzuki{at}nih.go.jp

{triangledown} Published ahead of print on 4 June 2008.

Journal of Virology, August 2008, p. 7964-7976, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00826-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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