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.
Mesh Terms:
Antiviral Agents, Benzoquinones, Cell Line, Tumor, HSP90 Heat-Shock Proteins, Hepacivirus, Humans, Lactams, Macrocyclic, Multiprotein Complexes, RNA, Viral, Tacrolimus Binding Proteins, Viral Nonstructural Proteins, Virus Replication
EMBO J.
Date: Oct. 18, 2006
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