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 Val121 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.
Highlights
Phosphoprotein characterized as a proline-rich hydrophilic and zinc-binding protein that regulates viral genomic RNA replication and viral particle assembly[4]
Our previous findings suggest that the tetratricopeptide repeat (TPR) domain of FKBP8 interacts with NS5A domain I in order to support Hepatitis C virus (HCV) replication[8,12]
We investigated a direct interaction between NS5A and FKBP6
Summary
Phosphoprotein characterized as a proline-rich hydrophilic and zinc-binding protein that regulates viral genomic RNA replication and viral particle assembly[4]. Hsp[90], which is highly conserved and ubiquitously expressed, contributes to conformational changes to endogenous proteins, including steroid receptors and cell signaling kinases[8,9]. Several members of the FK-506 binding protein (FKBP) family have TPR domains and exhibit the ability to bind Hsp[90] through interactions between the MEEVD motif and TPR. FKBP8 has the ability to bind to NS5A and Hsp[90] through its own TPR domains and is colocalized with NS5A, double-stranded RNA (dsRNA), Hsp[90], and other cochaperones such as FKBP8 within the convoluted membrane structure of infected cells[12]. FKBP8 may provide a client determinant for NS5A in order to maintain efficient viral replication. We determined involvement of FKBP4, FKBP5, and FKBP6 in NS5A binding and HCV replication
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