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Journal of Virology, February 2007, p. 1174-1185, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01684-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

E6AP Ubiquitin Ligase Mediates Ubiquitylation and Degradation of Hepatitis C Virus Core Protein{triangledown}

Masayuki Shirakura,1 Kyoko Murakami,1 Tohru Ichimura,2 Ryosuke Suzuki,1 Tetsu Shimoji,1 Kouichirou Fukuda,1 Katsutoshi Abe,1 Shigeko Sato,3 Masayoshi Fukasawa,3 Yoshio Yamakawa,3 Masahiro Nishijima,3 Kohji Moriishi,4 Yoshiharu Matsuura,4 Takaji Wakita,1 Tetsuro Suzuki,1 Peter M. Howley,5 Tatsuo Miyamura,1 and Ikuo Shoji1*

Department of Virology II,1 Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan,3 Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji-shi, Tokyo 192-0397, Japan,2 Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;,4 Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 021155

Received 4 August 2006/ Accepted 8 November 2006

Hepatitis C virus (HCV) core protein is a major component of viral nucleocapsid and a multifunctional protein involved in viral pathogenesis and hepatocarcinogenesis. We previously showed that the HCV core protein is degraded through the ubiquitin-proteasome pathway. However, the molecular machinery for core ubiquitylation is unknown. Using tandem affinity purification, we identified the ubiquitin ligase E6AP as an HCV core-binding protein. E6AP was found to bind to the core protein in vitro and in vivo and promote its degradation in hepatic and nonhepatic cells. Knockdown of endogenous E6AP by RNA interference increased the HCV core protein level. In vitro and in vivo ubiquitylation assays showed that E6AP promotes ubiquitylation of the core protein. Exogenous expression of E6AP decreased intracellular core protein levels and supernatant HCV infectivity titers in the HCV JFH1-infected Huh-7 cells. Furthermore, knockdown of endogenous E6AP by RNA interference increased intracellular core protein levels and supernatant HCV infectivity titers in the HCV JFH1-infected cells. Taken together, our results provide evidence that E6AP mediates ubiquitylation and degradation of HCV core protein. We propose that the E6AP-mediated ubiquitin-proteasome pathway may affect the production of HCV particles through controlling the amounts of viral nucleocapsid protein.

* 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: ishoji{at}nih.go.jp.

{triangledown} Published ahead of print on 15 November 2006.

Journal of Virology, February 2007, p. 1174-1185, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01684-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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