Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90

EMBO J. 2006 Oct 18;25(20):5015-25. doi: 10.1038/sj.emboj.7601367. Epub 2006 Oct 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Benzoquinones / pharmacology
  • Cell Line, Tumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • Hepacivirus / genetics
  • Hepacivirus / metabolism*
  • Humans
  • Lactams, Macrocyclic / pharmacology
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • RNA, Viral / biosynthesis*
  • RNA, Viral / genetics
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism*
  • Viral Nonstructural Proteins
  • Virus Replication / drug effects
  • Virus Replication / physiology*

Substances

  • Antiviral Agents
  • Benzoquinones
  • FKBP8 protein, human
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Multiprotein Complexes
  • NS-5 protein, hepatitis C virus
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Tacrolimus Binding Proteins
  • geldanamycin