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Journal of Virology, August 2009, p. 7959-7969, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00889-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human VAP-C Negatively Regulates Hepatitis C Virus Propagation{triangledown}

Hiroshi Kukihara,1 Kohji Moriishi,1 Shuhei Taguwa,1 Hideki Tani,1 Takayuki Abe,1 Yoshio Mori,1 Tetsuro Suzuki,2 Takasuke Fukuhara,1,3 Akinobu Taketomi,3 Yoshihiko Maehara,3 and Yoshiharu Matsuura1*

Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka,1 Department of Virology II, National Institute of Infectious Diseases, Tokyo,2 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan3

Received 3 May 2009/ Accepted 2 June 2009

Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) and subtype B (VAP-B) are involved in the regulation of membrane trafficking, lipid transport and metabolism, and the unfolded protein response. VAP-A and VAP-B consist of the major sperm protein (MSP) domain, the coiled-coil motif, and the C-terminal transmembrane anchor and form homo- and heterodimers through the transmembrane domain. VAP-A and VAP-B interact with NS5B and NS5A of hepatitis C virus (HCV) through the MSP domain and the coiled-coil motif, respectively, and participate in the replication of HCV. VAP-C is a splicing variant of VAP-B consisting of the N-terminal half of the MSP domain of VAP-B followed by the subtype-specific frameshift sequences, and its biological function has not been well characterized. In this study, we have examined the biological functions of VAP-C in the propagation of HCV. VAP-C interacted with NS5B but not with VAP-A, VAP-B, or NS5A in immunoprecipitation analyses, and the expression of VAP-C inhibited the interaction of NS5B with VAP-A or VAP-B. Overexpression of VAP-C impaired the RNA replication of the HCV replicon and the propagation of the HCV JFH1 strain, whereas overexpression of VAP-A and VAP-B enhanced the replication. Furthermore, the expression of VAP-C was observed in various tissues, whereas it was barely detected in the liver. These results suggest that VAP-C acts as a negative regulator of HCV propagation and that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation.

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

{triangledown} Published ahead of print on 10 June 2009.

Journal of Virology, August 2009, p. 7959-7969, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00889-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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