Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90.
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.
Okamoto
Toru
T
Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Nishimura
Yorihiro
Y
Ichimura
Tohru
T
Suzuki
Kensuke
K
Miyamura
Tatsuo
T
Suzuki
Tetsuro
T
Moriishi
Kohji
K
Matsuura
Yoshiharu
Y
D000998:Antiviral Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000096:biosynthesis* / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017361:Viral Nonstructural Proteins; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D046912:Multiprotein Complexes; D012367:RNA, Viral; D022021:Tacrolimus Binding Proteins; D017361:Viral Nonstructural Proteins; C471205:FKBP8 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C001277:geldanamycin