Herpes simplex virus ICP27 is required for virus-induced stabilization of the ARE-containing IEX-1 mRNA encoded by the human IER3 gene
Herpes simplex virus ICP27 is required for virus-induced stabilization of the ARE-containing IEX-1 mRNA encoded by the human IER3 gene
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DOI：
10.1128/jvi.01216-06
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发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Smiley, James R.
中科院分区：
文献类型：
--
作者：
Corcoran, Jennifer A.;Hsu, Wei-Li;Smiley, James R.
单纯疱疹病毒（HSV）在允许细胞的生产性感染期间抑制细胞基因表达，从而减少宿主对感染的反应。宿主关闭主要通过两种病毒蛋白ICP 27和病毒体宿主关闭（vhs）的互补作用来实现，这两种病毒蛋白分别抑制细胞mRNA生物合成和触发全局mRNA衰变。尽管大多数细胞mRNA因此被耗尽，但一些在感染后反而增加了丰度;也许令人惊讶的是，其中一些在其3 '非翻译区含有富含AU的不稳定元件（战神）。含有ARE的mRNA通常经历快速衰减;然而，它们的稳定性可以响应于激活p38/MK2促分裂原活化蛋白激酶（NLAPK）途径的信号（例如细胞因子和病毒感染）而增加。我们和其他人已经表明，HSV感染稳定ARE mRNA编码的应激诱导1 EX-1 mRNA，和以前的报告从另一个实验室已经表明，vhs是负责这种效果。然而，我们现在报道ICP 27对1 EX-1 mRNA的稳定是必不可少的，而vhs几乎没有作用。最近的一份报告证明，ICP 27激活p38 MAPK途径，我们通过使用一组携带一系列先前表征的ICP 27突变的I型单纯疱疹病毒（HSV-1）分离株，检测到这种活性与1 EX-1 mRNA的稳定之间存在强相关性。此外，1 EX-1 mRNA的稳定性被p38抑制剂SB 203580废除。总之，这些数据表明HSV-1立即早期蛋白ICP 27通过激活p38改变了含有ARE的信息1 EX-1的周转。由于许多ARE mRNA编码促炎细胞因子或其他立即早期反应蛋白，其中一些可能限制病毒复制，因此确定ICP 27是否介导许多或所有含ARE的mRNA的稳定将是非常有趣的。
Herpes simplex virus (HSV) stifles cellular gene expression during productive infection of permissive cells, thereby diminishing host responses to infection. Host shutoff is achieved largely through the complementary actions of two viral proteins, ICP27 and virion host shutoff (vhs), that inhibit cellular mRNA biogenesis and trigger global mRNA decay, respectively. Although most cellular mRNAs are thus depleted, some instead increase in abundance after infection; perhaps surprisingly, some of these contain AU-rich instability elements (AREs) in their 3'-untranslated regions. ARE-containing mRNAs normally undergo rapid decay; however, their stability can increase in response to signals such as cytokines and virus infection that activate the p38/MK2 mitogen-activated protein kinase (NLAPK) pathway. We and others have shown that HSV infection stabilizes the ARE mRNA encoding the stress-inducible 1EX-1 mRNA, and a previous report from another laboratory has suggested vhs is responsible for this effect. However, we now report that ICP27 is essential for 1EX-1 mRNA stabilization whereas vhs plays little if any role. A recent report has documented that ICP27 activates the p38 MAPK pathway, and we detected a strong correlation between this activity and stabilization of 1EX-1 mRNA by using a panel of HSV type I (HSV-1) isolates bearing an array of previously characterized ICP27 mutations. Furthermore, 1EX-1 mRNA stabilization was abrogated by the p38 inhibitor SB203580. Taken together, these data indicate that the HSV-1 immediate-early protein ICP27 alters turnover of the ARE-containing message 1EX-1 by activating p38. As many ARE mRNAs encode proinflammatory cytokines or other immediate-early response proteins, some of which may limit viral replication, it will be of great interest to determine if ICP27 mediates stabilization of many or all ARE-containing mRNAs.