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Journal of Virology, October 2003, p. 10237-10249, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10237-10249.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Proteasome Activator PA28{gamma}-Dependent Nuclear Retention and Degradation of Hepatitis C Virus Core Protein

Kohji Moriishi,1 Tamaki Okabayashi,1 Kousuke Nakai,1 Kyoji Moriya,2 Kazuhiko Koike,2 Shigeo Murata,3 Tomoki Chiba,3 Keiji Tanaka,3 Ryosuke Suzuki,4 Tetsuro Suzuki,4 Tatsuo Miyamura,4 and Yoshiharu Matsuura1*

Research Center for Emerging Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita-shi, Osaka 565-0871,1 Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655,2 Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613,3 Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan4

Received 9 April 2003/ Accepted 2 July 2003

Hepatitis C virus (HCV) core protein plays an important role in the formation of the viral nucleocapsid and a regulatory protein involved in hepatocarcinogenesis. In this study, we have identified proteasome activator PA28{gamma} (11S regulator {gamma}) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. These findings are extended to human HCV infection by the observation of this interaction in liver specimens from a patient with chronic HCV infection. Neither the interaction of HCV core protein with other PA28 subtypes nor that of PA28{gamma} with other Flavivirus core proteins was detected. Deletion of the PA28{gamma}-binding region from the HCV core protein or knockout of the PA28{gamma} gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28{gamma} enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28{gamma}-dependent pathway through which HCV pathogenesis may be exerted.

* Corresponding author. Mailing address: Research Center for Emerging Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1, Yamadaoka, Suita-shi, Osaka 565-0871, Japan. Phone: 81-6-6879-8340. Fax: 81-6-6879-8269. E-mail: matsuura{at}biken.osaka-u.ac.jp.

Journal of Virology, October 2003, p. 10237-10249, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10237-10249.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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