UL34 and herpes simplex virus envelopment

描述（由申请方提供）：疱疹病毒在细胞核中复制并包装其基因组。为了开始逃离细胞的过程，病毒必须首先通过一个称为初级出芽的过程进入内膜，从而穿过核膜。疱疹病毒的致病机制对人类健康具有重要意义。首先，这个过程代表了一个有吸引力的治疗靶点，因为它在许多方面不同于任何正常的细胞过程，对病毒是必需的，并且对所有疱疹病毒都是共同的。第二，核分裂机制改变了核膜的组织结构，为研究核膜的组织结构提供了有用的工具。 这里提出的研究建立在我们对单纯疱疹病毒UL34的研究基础上，UL34是生殖器的重要组成部分。从我们最初的资助阶段的结果表明，这种蛋白质在至少三个方面的抑制中起着关键作用，包括（i）病毒蛋白质的招募到核膜，（ii）阻止衣壳进入核膜的核膜组分的分散，以及（iii）核膜中核衣壳的包裹。 拟议研究的具体目标有三个方面 1.我们将通过表征一组已经在手的七个非功能性突变体UL34蛋白来定义UL34蛋白的基本功能，以及我们将通过保守残基的诱变产生的其他蛋白，以确定它们执行所需的各种功能的能力。 2.我们将描述UL34蛋白和其他参与表达的病毒蛋白之间的关键相互作用。这将包括实验，以测试的假设，即UL34介导的衣壳膜包裹，和筛选的相互作用UL34与其他病毒蛋白质，可能会参与到包装。 3.我们将充分表征与感染相关的宿主细胞核纤层的变化，并确定UL34和其他病毒蛋白实现这些变化的机制。

DESCRIPTION (provided by applicant): Herpesviruses replicate and package their genomes in the cell nucleus. In order to begin its process of escape from the cell, the virus must pass through the nuclear membrane by first budding into the inner nuclear membrane in a process called primary envelopment. The mechanism of herpesvirus envelopment is significant to human health from two points of view. First, this process represents an attractive target for therapy in that it is dissimilar in many ways to any normal cellular process, essential to the virus, and common to all herpesviruses. Second, the envelopment machinery alters the organization of the nuclear envelope and provides a useful tool for studying that organization. The research proposed here builds on our studies of herpes simplex virus UL34, an essential component of the envelopment apparatus. Results from our initial period of funding suggest that this protein plays critical roles in at least three aspects of envelopment including (i) recruitment of viral proteins to the nuclear envelope, (ii) dispersal of nuclear envelope components that prevent access of the capsid to the nuclear membrane, and (iii) wrapping of the nucleocapsid in the nuclear membrane. The specific goals of the proposed research are threefold 1. We will define essential functions of the UL34 protein by characterizing a set of seven non-functional mutant UL34 proteins already in hand, and others that we will generate by mutagenesis of conserved residues, for their ability to perform various functions required for envelopment. 2. We will characterize critical interactions between the UL34 protein and other viral proteins involved in envelopment. This will include experiments to test the hypothesis that UL34 mediates membrane wrapping of the capsid, and a screen for interactions of UL34 with other viral proteins that may participate in envelopment. 3. We will fully characterize changes in the host cell nuclear lamina associated with infection and determine the mechanism by which UL34 and other viral proteins accomplish those changes.