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Journal of Virology, May 2009, p. 5137-5147, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02179-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Involvement of Creatine Kinase B in Hepatitis C Virus Genome Replication through Interaction with the Viral NS4A Protein {triangledown}

Hiromichi Hara,1,2 Hideki Aizaki,1 Mami Matsuda,1 Fumiko Shinkai-Ouchi,3 Yasushi Inoue,1,4 Kyoko Murakami,1 Ikuo Shoji,1,5 Hayato Kawakami,6 Yoshiharu Matsuura,7 Michael M. C. Lai,8 Tatsuo Miyamura,1 Takaji Wakita,1 and Tetsuro Suzuki1*

Department of Virology II,1 Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan,3 Department of Internal medicine, Division of Pulmonary Diseases, The Jikei University School of Medicine, Tokyo 105-8461, Japan,2 Mita Hospital, International University of Health and Welfare, Tokyo 108-8329, Japan,4 Division of Microbiology, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan,5 Department of Anatomy, Kyorin University School of Medicine, Tokyo 181-8611, Japan,6 Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan,7 Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California 900338

Received 15 October 2008/ Accepted 20 February 2009

Persistent infection with hepatitis C virus (HCV) is a major cause of chronic liver diseases. The aim of this study was to identify host cell factor(s) participating in the HCV replication complex (RC) and to clarify the regulatory mechanisms of viral genome replication dependent on the host-derived factor(s) identified. By comparative proteome analysis of RC-rich membrane fractions and subsequent gene silencing mediated by RNA interference, we identified several candidates for RC components involved in HCV replication. We found that one of these candidates, creatine kinase B (CKB), a key ATP-generating enzyme that regulates ATP in subcellular compartments of nonmuscle cells, is important for efficient replication of the HCV genome and propagation of infectious virus. CKB interacts with HCV NS4A protein and forms a complex with NS3-4A, which possesses multiple enzyme activities. CKB upregulates both NS3-4A-mediated unwinding of RNA and DNA in vitro and replicase activity in permeabilized HCV replicating cells. Our results support a model in which recruitment of CKB to the HCV RC compartment, which has high and fluctuating energy demands, through its interaction with NS4A is important for efficient replication of the viral genome. The CKB-NS4A association is a potential target for the development of a new type of antiviral therapeutic strategy.

* 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 March 2009.

Journal of Virology, May 2009, p. 5137-5147, Vol. 83, No. 10
0022-538X/09/$08.00+0     doi:10.1128/JVI.02179-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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