Dephosphorylation of eIF-2α mediated by the γ134.5 protein of herpes simplex virus type 1 is required for viral response to interferon but is not sufficient for efficient viral replication
Dephosphorylation of eIF-2α mediated by the γ134.5 protein of herpes simplex virus type 1 is required for viral response to interferon but is not sufficient for efficient viral replication
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DOI：
10.1128/jvi.77.18.10154-10161.2003
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发表时间：
2003-09-01
影响因子：
5.4
通讯作者：
He, B
中科院分区：
文献类型：
--
作者：
Cheng, GF;Yang, K;He, B
单纯疱疹病毒1型(HSV-1)的Gamma(1)34.5蛋白具有阻断双链RNA依赖蛋白激酶(PKR)参与蛋白质合成的功能。在这个过程中，Gamma(1)34.5蛋白招募细胞蛋白磷酸酶1(PP1)形成一个高分子量的复合体，使eIF-2pha去磷酸化。在这里，我们表明，在没有任何其他病毒蛋白的情况下，Gamma(1)34.5蛋白能够介导eIF-2α去磷酸化。虽然从Gamma(1)34.5蛋白中删除1到52个氨基酸对eIF-2α去磷酸化没有影响，但进一步截短到146个氨基酸将极大地降低Gamma(1)34.5蛋白的活性。氨基酸188的额外截断是有害的，这表明仅有羧基末端结构域是不起作用的。与野生型HSV-1一样，氨基酸截短为1至52个氨基酸的Gamma(1)34.5突变体对干扰素具有抵抗力，对干扰素的抵抗力与eIF-2α去磷酸化有关。有趣的是，该突变体在感染细胞中表现出与伽马(1)34.5缺失突变体类似的生长缺陷。重组体中野生型Gamma(1)34.5基因的恢复完全逆转了表型。这些结果表明，由Gamma(1)34.5蛋白介导的eIF-2α去磷酸化是单纯疱疹病毒对干扰素应答所必需的，但不足以实现病毒复制。伽马(1)34.5蛋白的额外功能或活性有助于有效的病毒感染。
The gamma(1)34.5 protein of herpes simplex virus type 1 (HSV-1) functions to block the shutoff of protein synthesis involving double-stranded RNA-dependent protein kinase (PKR). In this process, the gamma(1)34.5 protein recruits cellular protein phosphatase 1 (PP1) to form a high-molecular-weight complex that dephosphorylates eIF-2alpha. Here we show that the gamma(1)34.5 protein is capable of mediating eIF-2alpha dephosphorylation without any other viral proteins. While deletion of amino acids 1 to 52 from the gamma(1)34.5 protein has no effect on eIF-2alpha dephosphorylation, further truncations up to amino acid 146 dramatically reduce the activity of the gamma(1)34.5 protein. An additional truncation up to amino acid 188 is deleterious, indicating that the carboxyl-terminal domain alone is not functional. Like wild-type HSV-1, the gamma(1)34.5 mutant with a truncation of amino acids 1 to 52 is resistant to interferon, and resistance to interferon is coupled to eIF-2alpha dephosphorylation. Intriguingly, this mutant exhibits a similar growth defect seen for the gamma(1)34.5 null mutant in infected cells. Restoration of the wild-type gamma(1)34.5 gene in the recombinant completely reverses the phenotype. These results indicate that eIF-2alpha dephosphorylation mediated by the gamma(1)34.5 protein is required for HSV response to interferon but is not sufficient for viral replication. Additional functions or activities of the gamma(1)34.5 protein contribute to efficient viral infection.