Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver
Altered proteolysis and global gene expression in hepatitis B virus X transgenic mouse liver
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DOI：
10.1128/jvi.80.3.1405-1413.2006
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发表时间：
2006-02-01
影响因子：
5.4
通讯作者：
Liang, TJ
中科院分区：
文献类型：
--
作者：
Hu, ZY;Zhang, ZS;Liang, TJ
B肝炎病毒X（HBX）是B肝炎病毒（HBV）在体内产生性感染所必需的，对宿主细胞具有多效性作用。我们以前已经证明，蛋白酶体复合物是HBX的细胞靶点，HBX改变蛋白酶体在体外的蛋白水解活性，蛋白酶体的抑制导致增强的病毒复制，这表明HBX和蛋白酶体相互作用在HBV的生命周期和发病机制中起着至关重要的作用。在本研究中，我们测试了HBX对体内蛋白酶体活性的影响，在转基因小鼠模型中，HBX的表达由小鼠肝脏中的主要尿启动子发育调节。此外，进行微阵列分析以检查HBX表达对肝脏的整体基因表达谱的影响。结果表明，HBX转基因小鼠肝脏中蛋白酶体的肽酶活性降低，而另一种细胞蛋白酶的活性升高，提示蛋白质降解的代偿机制。在微阵列分析中，不同的基因在HBX小鼠肝脏中发生了改变，并且具有显著变化的基因的数量随着年龄的增长而逐渐增加。功能聚类显示，参与转录和细胞生长的许多基因在HBX小鼠中受到显著影响，这可能是观察到的HBX多效性效应的原因。特别是，胰岛素样生长因子结合蛋白I在HBX小鼠肝脏中下调。在急性土拨鼠肝炎病毒感染期间也观察到类似的下调。其他变化包括蛋白水解相关基因的上调也可能导致HBV感染时肝功能的深刻改变。
Hepatitis B virus X (HBX) is essential for the productive infection of hepatitis B virus (HBV) in vivo and has a pleiotropic effect on host cells. We have previously demonstrated that the proteasome complex is a cellular target of HBX, that HBX alters the proteolytic activity of proteasome in vitro, and that inhibition of proteasome leads to enhanced viral replication, suggesting that HBX and proteasome interaction plays a crucial role in the life cycle and pathogenesis of HBV. In the present study, we tested the effect of HBX on the proteasome activities in vivo in a transgenic mouse model in which HBX expression is developmentally regulated by the mouse major urinary promoter in the liver. In addition, microarray analysis was performed to examine the effect of HBX expression on the global gene expression profile of the liver. The results showed that the peptidase activities of the proteasome were reduced in the HBX transgenic mouse liver, whereas the activity of another cellular protease was elevated, suggesting a compensatory mechanism in protein degradation. In the microarray analysis, diverse genes were altered in the HBX mouse livers and the number of genes with significant changes increased progressively with age. Functional clustering showed that a number of genes involved in transcription and cell growth were significantly affected in the HBX mice, possibly accounting for the observed pleiotropic effect of HBX. In particular, insulin-like growth factor-binding protein I was down-regulated in the HBX mouse liver. The down-regulation was similarly observed during acute woodchuck hepatitis virus infection. Other changes including up-regulation of proteolysis-related genes may also contribute to the profound alterations of liver functions in HBV infection.