The Herpes Simplex Virus 1 UL51 Gene Product Has Cell Type-Specific Functions in Cell-to-Cell Spread
The Herpes Simplex Virus 1 UL51 Gene Product Has Cell Type-Specific Functions in Cell-to-Cell Spread
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DOI：
10.1128/jvi.03707-13
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发表时间：
2014-01
影响因子：
5.4
通讯作者：
R. Roller;Alison C. Haugo;Kui Yang;J. Baines
中科院分区：
文献类型：
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作者：
R. Roller;Alison C. Haugo;Kui Yang;J. Baines
摘要 单纯疱疹病毒 1 (HSV-1) UL51 基因编码一种 244 个氨基酸 (aa) 的棕榈酰化蛋白，该蛋白在所有疱疹病毒中都是保守的。据报道，α疱疹病毒 UL51 (pUL51) 蛋白在核出口和细胞质包膜中发挥作用。由于 UL51 编码序列 5' 端与 UL52 启动子序列重叠，并未产生完全缺失，但 HSV 和伪狂犬病病毒 (PrV) 中产生的部分缺失表明在上皮细胞间传播中具有额外功能。在这里，我们以两种方式展示了 HSV-1 pUL51 的复制、释放和细胞间传播功能的部分解偶联。 pUL51 中氨基酸 73 至 244 被删除或 N 末端附近的保守 YXXΦ 基序被改变的病毒在传播中表现出细胞特异性缺陷，而这种缺陷不能用复制和病毒释放的缺陷来解释。此外，表达 C 末端增强型绿色荧光蛋白 (EGFP) 标记的 pUL51 的细胞系支持正常病毒复制并释放到培养基中，但仅形成小噬斑。该细胞系也无法支持 gE 正常定位到细胞连接处。 gE和pUL51部分共定位于感染细胞中，并且这两种蛋白可以从感染细胞中共免疫沉淀，表明它们可以在感染过程中形成复合物。与pUL51突变相关的细胞间传播缺陷比与gE无效病毒相关的细胞间传播缺陷更严重，表明pUL51在上皮细胞传播中具有不依赖于gE的功能。重要性 疱疹病毒在其宿主体内建立并从终生潜伏期重新激活。当它们重新激活时，尽管存在包括中和抗体在内的有效免疫反应，但它们仍能够在宿主内传播。这种能力部分源自病毒在细胞之间传播的特殊机制。细胞间传播是疱疹病毒的保守特性，可能依赖于保守的病毒基因。了解它们的功能可能有助于疫苗和疗法的设计。在这里，我们展示了保守的病毒基因之一 UL51，除了先前证明的在病毒组装中的作用之外，在细胞间传播中也具有重要作用。我们发现它的功能取决于被感染细胞的类型，并且我们发现它与另一种病毒传播因子 gE 相互作用并调节其功能。
ABSTRACT The herpes simplex virus 1 (HSV-1) UL51 gene encodes a 244-amino-acid (aa) palmitoylated protein that is conserved in all herpesviruses. The alphaherpesvirus UL51 (pUL51) protein has been reported to function in nuclear egress and cytoplasmic envelopment. No complete deletion has been generated because of the overlap of the UL51 coding sequence 5′ end with the UL52 promoter sequences, but partial deletions generated in HSV and pseudorabies virus (PrV) suggest an additional function in epithelial cell-to-cell spread. Here we show partial uncoupling of the replication, release, and cell-to-cell spread functions of HSV-1 pUL51 in two ways. Viruses in which aa 73 to 244 were deleted from pUL51 or in which a conserved YXXΦ motif near the N terminus was altered showed cell-specific defects in spread that cannot be accounted for by defects in replication and virus release. Also, a cell line that expresses C-terminally enhanced green fluorescent protein (EGFP)-tagged pUL51 supported normal virus replication and release into the medium but the formation of only small plaques. This cell line also failed to support normal localization of gE to cell junctions. gE and pUL51 partially colocalized in infected cells, and these two proteins could be coimmunoprecipitated from infected cells, suggesting that they can form a complex during infection. The cell-to-cell spread defect associated with the pUL51 mutation was more severe than that associated with gE-null virus, suggesting that pUL51 has gE-independent functions in epithelial cell spread. IMPORTANCE Herpesviruses establish and reactivate from lifelong latency in their hosts. When they reactivate, they are able to spread within their hosts despite the presence of a potent immune response that includes neutralizing antibody. This ability is derived in part from a specialized mechanism for virus spread between cells. Cell-to-cell spread is a conserved property of herpesviruses that likely relies on conserved viral genes. An understanding of their function may aid in the design of vaccines and therapeutics. Here we show that one of the conserved viral genes, UL51, has an important role in cell-to-cell spread in addition to its previously demonstrated role in virus assembly. We find that its function depends on the type of cell that is infected, and we show that it interacts with and modulates the function of another viral spread factor, gE.