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Article

  • The EMBO Journal (2006) 25, 5015 - 5025
  • doi:10.1038/sj.emboj.7601367

Published online: 5 October 2006

Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90

Toru Okamoto1, Yorihiro Nishimura2, Tohru Ichimura3, Kensuke Suzuki1, Tatsuo Miyamura2, Tetsuro Suzuki2, Kohji Moriishi1 and Yoshiharu Matsuura1

  1. Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
  2. Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
  3. Department of Chemistry, Graduate School of Sciences and Engineering, Tokyo Metropolitan University, Tokyo, Japan

Correspondence to:

Yoshiharu Matsuura, Department of Molecular Virology, Research Centre for Emerging Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita-chi, Osaka 565-0871, Japan. Tel.: +81 6 6879 8340; Fax: +81 6 6879 8269; E-mail: matsuura@biken.osaka-u.ac.jp

Received 3 November 2005; Accepted 27 July 2006

Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a component of viral replicase and is well known to modulate the functions of several host proteins. Here, we show that NS5A specifically interacts with FKBP8, a member of the FK506-binding protein family, but not with other homologous immunophilins. Three sets of tetratricopeptide repeats in FKBP8 are responsible for interactions with NS5A. The siRNA-mediated knockdown of FKBP8 in a human hepatoma cell line harboring an HCV RNA replicon suppressed HCV RNA replication, and this reduction was reversed by the expression of an siRNA-resistant FKBP8 mutant. Furthermore, immunoprecipitation analyses revealed that FKBP8 forms a complex with Hsp90 and NS5A. Treatment of HCV replicon cells with geldanamycin, an inhibitor of Hsp90, suppressed RNA replication in a dose-dependent manner. These results suggest that the complex consisting of NS5A, FKBP8, and Hsp90 plays an important role in HCV RNA replication.

  • Keywords:

    • FK506-binding protein,
    • geldanamycin,
    • hepatitis C virus,
    • Hsp90,
    • RNA replication