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

Authors :
Tatsuo Miyamura
Hiromichi Hara
Fumiko Shinkai-Ouchi
Yoshiharu Matsuura
Michael M. C. Lai
Kyoko Murakami
Mami Matsuda
Takaji Wakita
Tetsuro Suzuki
Hayato Kawakami
Yasushi Inoue
Ikuo Shoji
Hideki Aizaki
Source :
Journal of Virology. 83:5137-5147
Publication Year :
2009
Publisher :
American Society for Microbiology, 2009.

Abstract

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.

Details

ISSN :
10985514 and 0022538X
Volume :
83
Database :
OpenAIRE
Journal :
Journal of Virology
Accession number :
edsair.doi.dedup.....314edaddc7228012225e80547a26494a