C型肝炎ウイルス非構造蛋白NS4Aの翻訳抑制作用

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  • Translational Suppresion by Nonstructural Protein 4A of Hepatitis C Virus

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NS4A, which is a non-structural protein of hepatitis C virus, forms a stable complex with the NS3 proteinase and is required as a cofactor for cleavage at the 3/4A and 4B/5A sites, enhancing the processing at the 4A/4B and 5A/5B sites. NS4A is also involved in the hyperphosphorylation of NS5A. However, the other functions of NS4A are hardly understood. In this study, we demonstrated that NS4A suppressed the gene expression using CAT assay. To analyze the underlying mechanism, we perfomed semi-quantitative RT-PCR to determine transcription levels. Our results showed that NS4A did not suppress transcription, suggesting that the suppression of the gene expression was mediated post-transcriptionally by NS4A. The effect of NS4A on in vitro translation was then analyzed. The results obtained revealed that NS4A suppressed in vitro translation. In addition, the responsible region of NS4A to suppress translation was analyzed with deletion mutants of NS4A. Our results suggested that the amino-terminal 18 residues of NS4A played an important role in the translational suppression. Since NS3 is known to form a stable complex with NS4A, effects of NS3 on NS4A-mediated translational suppression were analyzed. NS4A-mediated translational suppression was partially negated by NS3 when NS3 was coexpressed in either trans or cis if, in the latter case, the junction between NS3 and NS4A could be cleaved. However, a mutant NS3/NS4A protein that was unable to cleave the junction still possessed the ability to suppress translation. It has been reported that the proteins of viruses such as poliovirus and adenovirus suppress protein expression of the host cell resulting in an ideal environment for infection. Similarly, it appears likely that HCV NS4A suppresses translation of the host cell to work favorably for the establishment of HCV infection.

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