ORCID Profile
0000-0002-3177-3503
Current Organisation
University of Tokyo
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Publisher: American Society for Microbiology
Date: 10-2003
DOI: 10.1128/JVI.77.19.10237-10249.2003
Abstract: Hepatitis C virus (HCV) core protein plays an important role in the formation of the viral nucleocapsid and a regulatory protein involved in hepatocarcinogenesis. In this study, we have identified proteasome activator PA28γ (11S regulator γ) as an HCV core binding protein by using yeast two-hybrid system. This interaction was demonstrated not only in cell culture but also in the livers of HCV core transgenic mice. These findings are extended to human HCV infection by the observation of this interaction in liver specimens from a patient with chronic HCV infection. Neither the interaction of HCV core protein with other PA28 subtypes nor that of PA28γ with other Flavivirus core proteins was detected. Deletion of the PA28γ-binding region from the HCV core protein or knockout of the PA28γ gene led to the export of the HCV core protein from the nucleus to the cytoplasm. Overexpression of PA28γ enhanced the proteolysis of the HCV core protein. Thus, the nuclear retention and stability of the HCV core protein is regulated via a PA28γ-dependent pathway through which HCV pathogenesis may be exerted.
Publisher: Proceedings of the National Academy of Sciences
Date: 30-01-2007
Abstract: Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28γ/REGγ regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28γ gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28γ-dependent manner. Heterodimer composed of liver X receptor α (LXRα) and retinoid X receptor α (RXRα) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXRα/RXRα to LXR-response element in the presence but not the absence of PA28γ. These findings suggest that PA28γ plays a crucial role in the development of liver pathology induced by HCV infection.
Publisher: American Society for Microbiology
Date: 15-02-2007
DOI: 10.1128/JVI.01683-06
Abstract: The hepatitis C virus (HCV) core protein is a component of nucleocapsids and a pathogenic factor for hepatitis C. Several epidemiological and experimental studies have suggested that HCV infection is associated with insulin resistance, leading to type 2 diabetes. We have previously reported that HCV core gene-transgenic (PA28γ +/+ CoreTg) mice develop marked insulin resistance and that the HCV core protein is degraded in the nucleus through a PA28γ-dependent pathway. In this study, we examined whether PA28γ is required for HCV core-induced insulin resistance in vivo. HCV core gene-transgenic mice lacking the PA28γ gene (PA28γ −/− CoreTg) were prepared by mating of PA28γ +/+ CoreTg with PA28γ-knockout mice. Although there was no significant difference in the glucose tolerance test results among the mice, the insulin sensitivity in PA28γ −/− CoreTg mice was recovered to a normal level in the insulin tolerance test. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), production of IRS2, and phosphorylation of Akt were suppressed in the livers of PA28γ +/+ CoreTg mice in response to insulin stimulation, whereas they were restored in the livers of PA28γ −/− CoreTg mice. Furthermore, activation of the tumor necrosis factor alpha promoter in human liver cell lines or mice by the HCV core protein was suppressed by the knockdown or knockout of the PA28γ gene. These results suggest that the HCV core protein suppresses insulin signaling through a PA28γ-dependent pathway.
No related grants have been discovered for Shigeo Murata.