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Effects of hepatitis C virus proteins on protein-tyrosine phosphorylation in liver cells

丙型肝炎病毒蛋白对肝细胞蛋白酪氨酸磷酸化的影响

基本信息

批准号：
18590293
负责人：
SADA Kiyonao
金额：
$ 2.48万
依托单位：
University of Fukui
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

The aim of this study is to investigate the effects of hepatitis C virus (HCV) proteins on protein-tyrosine phosphorylation, in particular, protein-tyrosine kinase Syk in vivo.In 2006, we identified that HCV non-structural protein 5A (NS5A) strongly interacted with Syk, and phospholipase C (PLC)-γ1 was the intracellular target of Syk in cultured liver cells (Huh-7 cells). Moreover, we investigated the pathological mechanism of HCV NS3 and NS4A, identification of novel SSPE virus, and characterization of virus-related ubiquitin ligase, and reported their results.In 2007, we found that interaction of NS5A with Syk was detected also in Huh-7.5 cells harboring an HCV RNA replicon and those infected with HCV (HCV J6/JFH-1). Deletion mutational analysis revealed that an N-terminal portion of NS5A was involved in the physical interaction with Syk. In vitro kinase assay demonstrated that NS5A inhibited enzymatic activity of Syk and that, in addition to the N-terminal 175 residues, a central portion of NS5A was required for the Syk inhibition. Moreover, immunohistochemical analysis revealed that endogenous Syk, which otherwise was expressed diffusely in the cytoplasm of normal hepatocytes, was localized near the cell membrane with a patched pattern in HCV-infected hepatocytes. Our results imply the possibility that NS5A is involved in the carcinogenesis of hepatocytes through the suppression of Syk, a potent tumor suppressor in human breast carcinoma. Furthermore, we investigated the pathogenesis of diabetes as a HCV complication and proteome analysis of HCV infection. Furthermore, we examined the role of novel adaptor protein 3BP2 and human inherited disease cherubism and published a review article.

本研究旨在探讨丙型肝炎病毒蛋白在体内对蛋白酪氨酸磷酸化，特别是蛋白酪氨酸激酶Syk的影响。2006年，我们在培养的肝细胞(Huh-7细胞)中发现，丙型肝炎病毒非结构蛋白5A(NS5A)与Syk有很强的相互作用，而磷脂酶C(PLC)-γ1是Syk的胞内靶点。此外，我们还研究了丙型肝炎病毒NS3和NS4A的病理机制、新的SSPE病毒的鉴定以及病毒相关泛素连接酶的特性，并报道了他们的结果。2007年，我们发现在携带丙型肝炎病毒RNA复制子的Huh-7.5细胞和感染丙型肝炎病毒的细胞(丙型肝炎病毒J6/JFH-1)中也检测到NS5A与Syk的相互作用。缺失突变分析表明，NS5A的N端部分参与了与Syk的物理相互作用。体外激酶实验表明，NS5A抑制Syk的活性，除了N端175个残基外，还需要NS5A的中心部分来抑制Syk的活性。免疫组织化学分析显示，在正常肝细胞胞浆中弥漫表达的内源性Syk蛋白定位于靠近细胞膜的区域，在丙型肝炎病毒感染的肝细胞中呈斑块状分布。我们的结果暗示，NS5A可能通过抑制Syk参与肝细胞癌的发生。Syk是一种有效的乳腺癌抑制因子。此外，我们还研究了作为丙型肝炎病毒并发症的糖尿病的发病机制以及丙型肝炎病毒感染的蛋白质组分析。此外，我们还研究了新的适配器蛋白3BP2与人类遗传性疾病畸形症的作用，并发表了一篇综述文章。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel mitochondria ubiquitin ligase plays a critical role in mitochondria] dynamics

一种新型线粒体泛素连接酶在线粒体动力学中发挥关键作用

DOI：
发表时间：
2006
期刊：
EMBO J 25(15)
影响因子：
0
作者：
Yonashiro;R.;Ishido;S.;Kyo;S.;Fukuda;T.;Goto;E.;Matsuki;Y.;Ohmura-Hashimoto;M.;Sada. K.;Hotta;H.;Yamamura;H.;Inatome;R.;Yanagi;S
通讯作者：
S

A high degree of sequence variation of HCV NS5A and the presence of anti-NS5A antibodies in the pretreatment sera are associated with efficient viral clearance by combination therapy using pegylated interferon and ribavirin

HCV NS5A 的高度序列变异和预处理血清中抗 NS5A 抗体的存在与聚乙二醇化干扰素和利巴韦林联合治疗的有效病毒清除相关