Multiple Lytic Origins of Replication Are Required for Optimal Gammaherpesvirus Fitness In Vitro and In Vivo.
Multiple Lytic Origins of Replication Are Required for Optimal Gammaherpesvirus Fitness In Vitro and In Vivo.
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DOI：
10.1371/journal.ppat.1005510
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发表时间：
2016-03
期刊：
影响因子：
6.7
通讯作者：
Adler H
中科院分区：
文献类型：
--
作者：
Sattler C;Steer B;Adler H
疱疹病毒生物学中一个未解决的问题是为什么某些疱疹病毒含有多个裂解性复制起点（oriLyt）。使用鼠伽马疱疹病毒 68 (MHV-68) 作为包含两个 oriLyt 的模型病毒，我们证明在体外和体内，两个 oriLyt 中的任何一个的丢失在某些情况下都可以很好地耐受，但在其他情况下则不然。这与细胞类型、器官或接种途径有关。根据细胞类型，不同的细胞蛋白，例如 Hexim1 和 Rbbp4，被发现与 oriLyt DNA 相关。这些蛋白质的过度表达或下调对缺乏左 oriLyt 的突变体的生长有不同的影响。因此，需要多个 oriLyt 以确保不同细胞类型和组织的最佳适应性。疱疹病毒在其生命周期中有两个阶段：裂解复制和潜伏期。裂解性 DNA 复制起始于病毒基因组上的特定位点，即所谓的裂解性复制起点 (oriLyt)。虽然一些疱疹病毒具有单个 oriLyt，但其他病毒则具有多个 oriLyt。为什么某些疱疹病毒需要不止一种 oriLyt 尚不清楚。这项研究表明，多个oriLyts的存在使得γ疱疹病毒能够在不同的细胞或组织类型以及病毒生命周期的不同阶段有效地建立感染。根据细胞类型的不同，不同的细胞蛋白被发现与 oriLyt DNA 相关，并且这些蛋白的过度表达或下调对仅含有单个 oriLyt 的病毒的生长产生不同的影响。因此，多个 oriLyt 可确保不同细胞类型和组织中的最佳病毒适应度。
An unresolved question in herpesvirus biology is why some herpesviruses contain more than one lytic origin of replication (oriLyt). Using murine gammaherpesvirus 68 (MHV-68) as model virus containing two oriLyts, we demonstrate that loss of either of the two oriLyts was well tolerated in some situations but not in others both in vitro and in vivo. This was related to the cell type, the organ or the route of inoculation. Depending on the cell type, different cellular proteins, for example Hexim1 and Rbbp4, were found to be associated with oriLyt DNA. Overexpression or downregulation of these proteins differentially affected the growth of mutants lacking either the left or the right oriLyt. Thus, multiple oriLyts are required to ensure optimal fitness in different cell types and tissues. Herpesviruses show two stages in their life cycle: lytic replication and latency. Lytic DNA replication is initiated at a defined site on the viral genome, the so-called lytic origin of replication (oriLyt). While some herpesviruses have a single oriLyt, others have multiple oriLyts. Why some herpesviruses need more than one oriLyt is not known. This study demonstrates that the presence of multiple oriLyts enables gammaherpesviruses to efficiently establish infection in different cell or tissue types and during different phases of the viral life cycle. Depending on the cell type, different cellular proteins were found to be associated with oriLyt DNA, and overexpression or downregulation of these proteins differentially affected the growth of viruses containing only a single oriLyt. Thus, multiple oriLyts ensure optimal viral fitness in different cell types and tissues.