Herpes simplex virus-mediated regulation of host gene expression

项目总结： 单纯疱疹病毒1型(HSV-1)是一种高度传染性的病原体，可引起许多 从疼痛的皮肤病到角膜炎和脑炎的各种疾病。基因 HSV-1的表达程序在过去的几年里得到了广泛的研究 几十年。然而，尽管进行了密集的努力，目前仍不清楚HSV-1如何 抑制宿主基因的表达，以实现有效的病毒复制。基因研究已经 证明了ICP27，由一个重要的即刻早期基因编码，扮演着一个 在抑制宿主信使核糖核酸生物发生中的重要作用。基于体外测试，早些时候 研究表明，ICP27可以阻止宿主基因的转录和剪接。 通过高通量分析HSV-1感染后宿主基因的表达或 然而，最近的研究发现，ICP27的过度表达没有发现任何一种全局抑制 转录或剪接，但剪接只改变了一小部分基因。 有趣的是，这些研究发现，有广泛的转录终止 这种抑制是宿主基因所特有的。 尽管这些最近的研究为HSV-1诱导的宿主提供了重要的见解 关闭，HSV-1介导的转录阻断的分子机制 终端仍然完全未知，目前还不清楚这样的阻塞是否 是有效复制病毒所必需的。我们的目标是在以下方面解决这些重要问题 这项提议。在我们的初步研究中，我们发现ICP27与 必需信使核糖核酸3‘加工因子CPSF和ICP27阻断信使核糖核酸3’ 正在处理。由于转录终止需要mRNA3‘处理，我们将 验证ICP27通过阻断mRNA来抑制宿主转录终止的假设 通过CPSF的3‘处理，以及ICP27介导的宿主mRNA处理的中断 对HSV复制很重要。

Project summary: Herpes simplex virus 1 (HSV-1) is a highly contagious pathogen that causes a number of diseases ranging from painful skin lesions to keratitis and encephalitis. The gene expression program of HSV-1 has been extensively studied for the past several decades. Despite the intensive effort, however, it remains unclear how HSV-1 suppresses host gene expression to allow efficient viral replication. Genetic studies have demonstrated that ICP27, encoded by an essential immediate early gene, plays an essential role in the inhibition of host mRNA biogenesis. Based on in vitro assays, earlier studies have suggested that ICP27 blocks transcription and splicing of host genes. Through high throughput analyses of host gene expression following HSV-1 infection or ICP27 overexpression, however, recent studies detected no global inhibition of either transcription or splicing, but only splicing changes in a small number of genes. Interestingly, these studies found that there was widespread transcription termination defect in HSV-1-infected cells and that this inhibition was specific to host genes. Although these recent studies provided important insight into HSV-1-induced host shutoff, the molecular mechanisms underlying HSV-1-mediated block of transcription termination remain completely unknown and it is unclear whether such a block is required for efficient viral replication. We aim to address these important questions in this proposal. In our preliminary studies, we found that ICP27 specifically interacts with the essential mRNA 3' processing factor CPSF and that ICP27 blocks mRNA 3' processing. Since mRNA 3' processing is required for transcription termination, we will test the hypothesis that ICP27 inhibits host transcription termination by blocking mRNA 3' processing via CPSF, and that ICP27-mediated disruption of host mRNA processing is important for HSV replication.