Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis
Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis
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DOI：
10.1073/pnas.0607312104
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发表时间：
2007-01-30
影响因子：
11.1
通讯作者：
Matsuura, Yoshiharu
中科院分区：
文献类型：
--
作者：
Moriishi, Kohji;Mochizuki, Rika;Matsuura, Yoshiharu
丙型肝炎病毒（HCV）是慢性肝病的主要病因，经常导致脂肪变性、肝硬化，最终导致肝细胞癌（HCC）。HCV核心蛋白不仅是病毒颗粒的组成部分，而且是一种多功能蛋白，因为HCV核心基因转基因（CoreTg）小鼠可发生肝脂肪变性和HCC。蛋白酶体激活剂PA28 γ /REG γ调节宿主和病毒蛋白，如核激素受体和HCV核心蛋白。本研究表明，敲除PA28 γ基因可诱导CoreTg小鼠肝细胞核中HCV核心蛋白的积累，并破坏肝脂肪变性和HCC的发展。此外，HCV核心蛋白在细胞系和小鼠肝脏中以pa28y依赖的方式上调脂肪酸生物合成和srebp-1c启动子活性相关基因。已知由肝X受体α (LXR α)和类视黄醇X受体α (RXR α)组成的异源二聚体可上调srebp-1c启动子活性。我们的数据还表明，HCV核心蛋白在PA28 γ存在而不存在的情况下增强了LXR α /RXR α与LXR反应元件的结合。这些发现表明PA28 γ在HCV感染引起的肝脏病理发展中起着至关重要的作用。
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 PA28 gamma/REG gamma regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28 gamma 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 PA28y-dependent manner. Heterodimer composed of liver X receptor alpha (LXR alpha) and retinoid X receptor alpha (RXR alpha) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXR alpha/RXR alpha to LXR-response element in the presence but not the absence of PA28 gamma. These findings suggest that PA28 gamma plays a crucial role in the development of liver pathology induced by HCV infection.