Cochaperone activity of human butyrate-induced transcript 1 facilitates hepatitis C virus replication through an Hsp90-dependent pathway.
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a component of the replication complex consisting of several host and viral proteins. We have previously reported that human butyrate-induced transcript 1 (hB-ind1) recruits heat shock protein 90 (Hsp90) and FK506-binding protein 8 (FKBP8) to the replication complex through interaction with NS5A. To gain more insights into the biological functions of hB-ind1 in HCV replication, we assessed the potential cochaperone-like activity of hB-ind1, because it has significant homology with cochaperone p23, which regulates Hsp90 chaperone activity. The chimeric p23 in which the cochaperone domain was replaced with the p23-like domain of hB-ind1 exhibited cochaperone activity comparable to that of the authentic p23, inhibiting the glucocorticoid receptor signaling in an Hsp90-dependent manner. Conversely, the chimeric hB-ind1 in which the p23-like domain was replaced with the cochaperone domain of p23 resulted in the same level of recovery of HCV propagation as seen in the authentic hB-ind1 in cells with knockdown of the endogenous hB-ind1. Immunofluorescence analyses revealed that hB-ind1 was colocalized with NS5A, FKBP8, and double-stranded RNA in the HCV replicon cells. HCV replicon cells exhibited a more potent unfolded-protein response (UPR) than the parental and the cured cells upon treatment with an inhibitor for Hsp90. These results suggest that an Hsp90-dependent chaperone pathway incorporating hB-ind1 is involved in protein folding in the membranous web for the circumvention of the UPR and that it facilitates HCV replication.
Taguwa
Shuhei
S
Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita-shi, Osaka, Japan.
Kambara
Hiroto
H
Omori
Hiroko
H
Tani
Hideki
H
Abe
Takayuki
T
Mori
Yoshio
Y
Suzuki
Tetsuro
T
Yoshimori
Tamotsu
T
Moriishi
Kohji
K
Matsuura
Yoshiharu
Y
D002460:Cell Line; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D006836:Hydro-Lyases; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000821:virology; D008099:Liver / Q000166:cytology / Q000821:virology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017510:Protein Folding; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C410722:HACD3 protein, human; D006836:Hydro-Lyases