The y134.5 gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells-猫眼课题宝

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J. Chou;B. Roizman

单纯疱疹病毒 1 的 yv34.5 基因先前已被证明在病毒 vPrulence 中发挥作用，因为删除该基因会使病毒在中枢神经系统中复制的能力降低 4100,000 倍，并导致小鼠死亡。在这里，我们表明，在人神经母细胞瘤细胞中，神经元起源的 SK-N-SH 134.5 无效突变体表达早期蛋白、病毒 IQNA 和晚期基因的 mRNA。然而，病毒 I.NA 合成的开始引发了放射性前体掺入蛋白质的完全停止。突变型和野生型病毒在非神经元来源的细胞系或细胞株中复制且不能分化。结果表明，在缺乏 y,34.5 基因的情况下，SK-N-SH 神经母细胞瘤细胞触发了类似于代谢应激诱导的神经元细胞程序性细胞死亡的反应。 yi34.5 蛋白可能阻止这种细胞反应，以便实现病毒复制所需的蛋白质合成。单纯疱疹病毒 1 (HSV-1) 感染最严重和最具破坏性的表现是脑炎，250,000 名成年人中有 4 人患有脑炎 (1)。与这种疾病相关的令人相当感兴趣的是赋予病毒在中枢神经系统（CNS）组织中复制能力的基因。周等人。 (2) 报道称，称为 y134.5 的病毒基因使病毒能够在小鼠 CNS 中繁殖和传播，尽管它对于细胞培养物和至少在迄今为止测试的一些小鼠组织中的病毒复制不是必需的（R. J. Whitley、E. R. Kern、S. Chatterjee、J.C. 和 B.R.，未发表的数据）。 y134.5 基因位于病毒 DNA 长成分两侧的反向重复序列中，因此该基因在每个基因组中存在两个拷贝 (4-7)（见图 1）。它的位置与之前的报告一致，显示影响病毒在 CNS 组织中繁殖能力的位点位于原型排列中 HSV DNA 长组件的右端 (2, 8-11)。在旨在确定'y134.5基因产物的功能的研究过程中，我们发现用不能表达y134.5基因的突变体感染神经元来源的细胞会导致细胞蛋白质合成的关闭，而用野生型或突变体病毒感染非神经元来源的细胞导致持续的蛋白质合成和感染性后代的产生。（本文报告的一些结果于 1991 年 7 月 7-12 日在加利福尼亚州阿西洛玛举行的第 15 届国际疱疹病毒研讨会上发表。）最初从美国典型培养物保藏中心 (ATCC) 获得的 Vero 细胞在含有 b blVa'c' c a HSV-1(F) I J I 的 Dulbecco 改良 Eagle 培养基（DME 培养基）中繁殖

The yv34.5 gene of herpes simplex virus 1 was previously shown to play a role in viral vPrulence since deletion of the gene reduced by a factor of 4100,000 the capacit of the virus to replicate in the central nervous system and cause mortality in the mouse. Here we show that in the human neuroblastoma cell ling SK-N-SH ofneuronal origin 134.5 null mutants expressed early proteins, viral IQNA, and mRNA of late genes. However, the onset of viral I.NA synthesis triggered complete cessation of incorporation of radioactiyp preursors into proteins. The mutant and wild-type virus replicated and could not be differentiated in cell lines or cell striins of nonneuronal origin. The results indicate that in the absence of the y,34.5 gene' the SK-N-SH neuroblastoma cells triggered a response similar to the programed cell death of neuronal cells induced by metabolic stress. The yi34.5 protein precludes this cell response possibly in order to enable the protein synthesis necessary for viral replication. The most severe and devastating manifestation of herpes simplex virus 1 (HSV-1) infection is encephalitis, which afflicts '4 in 250,000 adults (1). Of considerable interest in connection with this disease are the genes that confer upon the virus the capacity to replicate in the central nervous system (CNS) tissues. Chou et al. (2) reported that a viral gene designated as y134.5 enables the virus to multiply and spread in the CNS of mice even though it is not essential for viral replication in cell culture and in at least some murine tissues tested to date (R. J. Whitley, E. R. Kern, S. Chatterjee, J.C., and B.R., unpublished data). The y134.5 gene is located in the inverted repeats flanking the long component of viral DNA and therefore the gene is present in two copies per genome (4-7) (see Fig. 1). Its location is consistent with previous reports showing that a locus that affected the capacity of the virus to multiply in the CNS tissues mapped at the right end of the long component of HSV DNA in the prototype arrangement (2, 8-11). In the course of studies designed to determine the function of the 'y134.5 gene product, we discovered that infection of cells of neuronal origin with mutants incapable of expressing the y134.5 gene resulted in shutoffofcellular protein synthesis, whereas infection ofcells ofnonneuronal origin with wild-type or mutant viruses resulted in sustained protein synthesis and production of infectious progeny. (Some of the results reported in this article were presented at the 15th Internatiqnal Herpesvirus Workshop, July 7-12, 1991, Asilomar, CA.), MATERIALS AND METHODS Cels. Vero cells originally obtained from the American Type Culture Collection (ATCC) were propagated in Dulbecco's modified Eagle's medium (DME medium) containing a b blVa'c' c a HSV-1(F) I J I

The y134.5 gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells

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