Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90

Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
The EMBO Journal (Impact Factor: 10.75). 11/2006; 25(20):5015-25. DOI: 10.1038/sj.emboj.7601367
Source: PubMed

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.

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Available from: Kohji Moriishi, Sep 05, 2015
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    • "Although previous reports have shown that host factors such as VAMP-associated protein (VAP)-A, VAP-B, cyclophilin A, FK506 binding protein 8, and heat shock protein 90 participate in HCV replication, these molecules are unlikely to participate in the determination of the liver tropism of HCV, owing to their ubiquitous expression [46, 77–79]. As described above, miR-122 is abundantly expressed specifically in hepatocytes and is essential for the efficient replication of HCV. "
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    ABSTRACT: Hepatitis C virus (HCV) exhibits a narrow host range and a specific tissue tropism. Mice expressing major entry receptors for HCV permit viral entry, and therefore the species tropism of HCV infection is considered to be reliant on the expression of the entry receptors. However, HCV receptor candidates are expressed and replication of HCV-RNA can be detected in several nonhepatic cell lines, suggesting that nonhepatic cells are also susceptible to HCV infection. Recently it was shown that the exogenous expression of a liver-specific microRNA, miR-122, facilitated the efficient replication of HCV not only in hepatic cell lines, including Hep3B and HepG2 cells, but also in nonhepatic cell lines, including Hec1B and HEK-293T cells, suggesting that miR-122 is required for the efficient replication of HCV in cultured cells. However, no infectious particle was detected in the nonhepatic cell lines, in spite of the efficient replication of HCV-RNA. In the nonhepatic cells, only small numbers of lipid droplets and low levels of very-low-density lipoprotein-associated proteins were observed compared with findings in the hepatic cell lines, suggesting that functional lipid metabolism participates in the assembly of HCV. Taken together, these findings indicate that miR-122 and functional lipid metabolism are involved in the tissue tropism of HCV infection. In this review, we would like to focus on the role of miR-122 and lipid metabolism in the cell tropism of HCV.
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    • "HSP90, which can cooperate with other proteins such as p23 and HSP70, has 2–4 copies existing internally in a duck liver virus particle, and might be related to interaction between virus polymerase [68]. Besides, it has been proposed that HSP90 is a major host factor for viral replication of many RNA viruses [69], implying a important role of HSP90 in NDV replication. "
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    • "Some cyclophilins and FKBP8 were shown to interact with NS5B and/or NS5A and to regulate HCV replication (Watashi et al., 2005; Okamoto et al., 2006), suggesting that immunophilins could lead to promising therapies for chronic hepatitis C, as discussed below. "
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    ABSTRACT: Hepatitis C virus (HCV), which is a major causative agent of blood-borne hepatitis, has chronically infected about 170 million individuals worldwide and leads to chronic infection, resulting in development of steatosis, cirrhosis, and eventually hepatocellular carcinoma. Hepatocellular carcinoma associated with HCV infection is not only caused by chronic inflammation, but also by the biological activity of HCV proteins. HCV core protein is known as a main component of the viral nucleocapsid. It cooperates with host factors and possesses biological activity causing lipid alteration, oxidative stress, and progression of cell growth, while other viral proteins also interact with host proteins including molecular chaperones, membrane-anchoring proteins, and enzymes associated with lipid metabolism to maintain the efficiency of viral replication and production. HCV core protein is localized on the surface of lipid droplets in infected cells. However, the role of lipid droplets in HCV infection has not yet been elucidated. Several groups recently reported that other viral proteins also support viral infection by regulation of lipid droplets and core localization in infected cells. Furthermore, lipid components are required for modification of host factors and the intracellular membrane to maintain or up-regulate viral replication. In this review, we summarize the current status of knowledge regarding the exploitation of lipid components by viral and host proteins in HCV infection.
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