Role of the Herpes Simplex Virus 1 Us3 Kinase Phosphorylation Site and Endocytosis Motifs in the Intracellular Transport and Neurovirulence of Envelope Glycoprotein B
Role of the Herpes Simplex Virus 1 Us3 Kinase Phosphorylation Site and Endocytosis Motifs in the Intracellular Transport and Neurovirulence of Envelope Glycoprotein B
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DOI：
10.1128/jvi.02314-10
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发表时间：
2011-05-01
影响因子：
5.4
通讯作者：
Kawaguchi, Yasushi
中科院分区：
文献类型：
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作者：
Imai, Takahiko;Arii, Jun;Kawaguchi, Yasushi
单纯疱疹病毒1（HSV-1）Us 3蛋白激酶使感染细胞中包膜糖蛋白B（gB）的胞质尾区中位置887（Thr-887）处的苏氨酸磷酸化。这种磷酸化下调gB的细胞表面表达，并在小鼠疱疹性基质角膜炎模型中的病毒发病机制中发挥作用。在本研究中，我们证明了Us 3磷酸化gB Thr-887上调内吞gB从感染细胞表面的积累。我们还表明，gB的胞质尾部，酪氨酸在位置889（Tyr-889）和双亮氨酸在位置871和872，两个基序是必需的gB细胞表面表达的有效下调和内吞gB在感染细胞中的积累上调。对gB中这三个序列突变的系统分析表明，感染细胞表面上gB的表达部分地通过增加内吞gB的积累而下调，内吞gB的积累由三个gB运输信号协调且紧密地调节。Tyr-889似乎在调节gB的细胞内转运中具有主要重要性，并且与脑内感染后小鼠中的HSV-1神经毒力有关。这些观察结果支持了HSV-1进化出三个gB序列以适当调节gB细胞内转运的假设，并且这种调节在HSV-1发病机制的不同方面起着关键作用。
Herpes simplex virus 1 (HSV-1) Us3 protein kinase phosphorylates threonine at position 887 (Thr-887) in the cytoplasmic tail of envelope glycoprotein B (gB) in infected cells. This phosphorylation downregulates cell surface expression of gB and plays a role in viral pathogenesis in the mouse herpes stromal keratitis model. In the present study, we demonstrated that Us3 phosphorylation of gB Thr-887 upregulated the accumulation of endocytosed gB from the surfaces of infected cells. We also showed that two motifs in the cytoplasmic tail of gB, tyrosine at position 889 (Tyr-889) and dileucines at positions 871 and 872, were required for efficient downregulation of gB cell surface expression and upregulation of accumulation of endocytosed gB in infected cells. A systematic analysis of mutations in these three sequences in gB suggested that the expression of gB on the surfaces of infected cells was downregulated in part by the increase in the accumulation of endocytosed gB, which was coordinately and tightly regulated by the three gB trafficking signals. Tyr-889 appeared to be of predominant importance in regulating the intracellular transport of gB and was linked to HSV-1 neurovirulence in mice following intracerebral infection. These observations support the hypothesis that HSV-1 evolved the three gB sequences for proper regulation of gB intracellular transport and that this regulation plays a critical role in diverse aspects of HSV-1 pathogenesis.