title: Cochaperone activity of human butyrate-induced transcript 1 facilitates hepatitis C virus replication through an Hsp90-dependent pathway.
abstract: 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.
authors: Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Suita-shi, Osaka, Japan.
authors: Shuhei
authors: S
authors: Taguwa
authors: Hiroto
authors: H
authors: Kambara
authors: Hiroko
authors: H
authors: Omori
authors: Hideki
authors: H
authors: Tani
authors: Takayuki
authors: T
authors: Abe
authors: Yoshio
authors: Y
authors: Mori
authors: Tetsuro
authors: T
authors: Suzuki
authors: Tamotsu
authors: T
authors: Yoshimori
authors: Kohji
authors: K
authors: Moriishi
authors: Yoshiharu
authors: Y
authors: Matsuura
mesh_terms: 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*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C410722:HACD3 protein, human; D006836:Hydro-Lyases