Involvement of FKBP6 in hepatitis C virus replication

Sci Rep. 2015 Nov 16:5:16699. doi: 10.1038/srep16699.

Abstract

The chaperone system is known to be exploited by viruses for their replication. In the present study, we identified the cochaperone FKBP6 as a host factor required for hepatitis C virus (HCV) replication. FKBP6 is a peptidyl prolyl cis-trans isomerase with three domains of the tetratricopeptide repeat (TPR), but lacks FK-506 binding ability. FKBP6 interacted with HCV nonstructural protein 5A (NS5A) and also formed a complex with FKBP6 itself or FKBP8, which is known to be critical for HCV replication. The Val(121) of NS5A and TPR domains of FKBP6 were responsible for the interaction between NS5A and FKBP6. FKBP6 was colocalized with NS5A, FKBP8, and double-stranded RNA in HCV-infected cells. HCV replication was completely suppressed in FKBP6-knockout hepatoma cell lines, while the expression of FKBP6 restored HCV replication in FKBP6-knockout cells. A treatment with the FKBP8 inhibitor N-(N', N'-dimethylcarboxamidomethyl)cycloheximide impaired the formation of a homo- or hetero-complex consisting of FKBP6 and/or FKBP8, and suppressed HCV replication. HCV infection promoted the expression of FKBP6, but not that of FKBP8, in cultured cells and human liver tissue. These results indicate that FKBP6 is an HCV-induced host factor that supports viral replication in cooperation with NS5A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cycloheximide / analogs & derivatives
  • Cycloheximide / pharmacology
  • HEK293 Cells
  • Hepacivirus / physiology*
  • Humans
  • Microscopy, Fluorescence
  • Protein Interaction Domains and Motifs
  • Protein Multimerization / drug effects
  • RNA Interference
  • RNA, Double-Stranded / metabolism
  • RNA, Small Interfering / metabolism
  • Tacrolimus Binding Proteins / antagonists & inhibitors
  • Tacrolimus Binding Proteins / genetics
  • Tacrolimus Binding Proteins / metabolism*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication*

Substances

  • FKBP6 protein, human
  • FKBP8 protein, human
  • N-(N',N'-dimethylcarboxamidomethyl)cycloheximide
  • RNA, Double-Stranded
  • RNA, Small Interfering
  • Viral Nonstructural Proteins
  • Cycloheximide
  • NS-5 protein, hepatitis C virus
  • Tacrolimus Binding Proteins