Nonstructural 3/4A Protease of Hepatitis C Virus Activates Epithelial Growth Factor-Induced Signal Transduction by Cleavage of the T-Cell Protein Tyrosine Phosphatase
Nonstructural 3/4A Protease of Hepatitis C Virus Activates Epithelial Growth Factor-Induced Signal Transduction by Cleavage of the T-Cell Protein Tyrosine Phosphatase
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DOI：
10.1002/hep.22857
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发表时间：
2009-06-01
期刊：
影响因子：
13.5
通讯作者：
Bode, Johannes Georg
中科院分区：
文献类型：
--
作者：
Brenndorfer, Erwin Daniel;Karthe, Juliane;Bode, Johannes Georg
丙型肝炎病毒（HCV）是世界范围内慢性肝病的主要原因，具有建立持续感染的高趋势。为了允许病毒基因组通过细胞翻译机制持续复制而不影响宿主细胞活力，病毒必须开发出一方面控制充分病毒复制所需的细胞级联反应，另一方面使病毒复制适应细胞要求的机制。本研究旨在进一步阐明HCV靶向宿主细胞生长因子信号传导的机制及其对病毒复制的影响。这项研究描述了一种新的机制，HCV通过非结构（NS）3/4A依赖性下调普遍表达的酪氨酸磷酸酶T细胞蛋白酪氨酸磷酸酶（TC-PTP）影响上皮生长因子受体/Akt通路的激活。NS 3/4A被证明在体外在两个切割位点处依赖于TC-PTP蛋白酶切割。这一发现的体内相关性得到了以下事实的支持，即TC-PTP蛋白表达的下调也可以在HCV感染的个体和肝内表达NS 3/4A的转基因小鼠中得到证实。结论：TC-PTP的这种下调导致上皮生长因子（EGF）诱导的信号转导的增强，并增加Akt的基础活性，这被证明是维持足够的病毒复制所必需的。因此，NS 3/4A的治疗靶向不仅可以通过阻断病毒多蛋白的加工来干扰病毒复制，而且还可以发挥不可预见的间接抗病毒作用，进一步减少病毒复制。（《肝脏病学》2009年;49：1810-1820）
The hepatitis C virus (HCV) is a worldwide major cause of chronic liver disease with a high tendency to establish a persistent infection. To permit persistent replication of viral genomes through the cellular translation machinery without affecting host cell viability, viruses must have developed mechanisms to control cellular cascades required for sufficient viral replication, on the one hand, and to adapt viral replication to the cellular requirements on the other hand. The present study aimed to further elucidate mechanisms by which HCV targets growth factor signaling of the host cell and their implications for viral replication. The study describes a novel mechanism by which HCV influences the activation of the epithelial growth factor receptor/Akt pathway through a nonstructural (NS)3/4A-dependent down-regulation of the ubiquitously expressed tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP). NS3/4A is demonstrated to cleave TC-PTP protease-dependently in vitro at two cleavage sites. The in vivo relevance of this finding is supported by the fact that down-regulation of TC-PTP protein expression could also be demonstrated in HCV-infected individuals and in transgenic mice with intrahepatic expression of NS3/4A. Conclusion: This down-regulation of TC-PTP results in an enhancement of epithelial growth factor (EGF)-induced signal transduction and increases basal activity of Akt, which is demonstrated to be essential for the maintenance of sufficient viral replication. Hence, therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects, further diminishing viral replication. (HEPATOLOGY 2009;49:1810-1820.)