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Journal of Virology, October 2009, p. 10427-10436, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01035-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cochaperone Activity of Human Butyrate-Induced Transcript 1 Facilitates Hepatitis C Virus Replication through an Hsp90-Dependent Pathway{triangledown}

Shuhei Taguwa,1 Hiroto Kambara,1 Hiroko Omori,2 Hideki Tani,1 Takayuki Abe,1 Yoshio Mori,1 Tetsuro Suzuki,3 Tamotsu Yoshimori,2 Kohji Moriishi,1 and Yoshiharu Matsuura1*

Department of Molecular Virology,1 Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Osaka,2 Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan3

Received 21 May 2009/ Accepted 27 July 2009

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a component of the replication complex consisting of several host and viral proteins. We have previously reported that human butyrate-induced transcript 1 (hB-ind1) recruits heat shock protein 90 (Hsp90) and FK506-binding protein 8 (FKBP8) to the replication complex through interaction with NS5A. To gain more insights into the biological functions of hB-ind1 in HCV replication, we assessed the potential cochaperone-like activity of hB-ind1, because it has significant homology with cochaperone p23, which regulates Hsp90 chaperone activity. The chimeric p23 in which the cochaperone domain was replaced with the p23-like domain of hB-ind1 exhibited cochaperone activity comparable to that of the authentic p23, inhibiting the glucocorticoid receptor signaling in an Hsp90-dependent manner. Conversely, the chimeric hB-ind1 in which the p23-like domain was replaced with the cochaperone domain of p23 resulted in the same level of recovery of HCV propagation as seen in the authentic hB-ind1 in cells with knockdown of the endogenous hB-ind1. Immunofluorescence analyses revealed that hB-ind1 was colocalized with NS5A, FKBP8, and double-stranded RNA in the HCV replicon cells. HCV replicon cells exhibited a more potent unfolded-protein response (UPR) than the parental and the cured cells upon treatment with an inhibitor for Hsp90. These results suggest that an Hsp90-dependent chaperone pathway incorporating hB-ind1 is involved in protein folding in the membranous web for the circumvention of the UPR and that it facilitates HCV replication.

* Corresponding author. Mailing address: Department of Molecular Virology, 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

{triangledown} Published ahead of print on 5 August 2009.

Journal of Virology, October 2009, p. 10427-10436, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.01035-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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