Inhibition of host and viral translation during vesicular stomatitis virus infection - eIF2 is responsible for the inhibition of viral but not host translation
Inhibition of host and viral translation during vesicular stomatitis virus infection - eIF2 is responsible for the inhibition of viral but not host translation
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DOI：
10.1074/jbc.m501156200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Lyles, DS
中科院分区：
文献类型：
--
作者：
Connor, JH;Lyles, DS
在允许水疱性口炎病毒（VSV）复制的细胞中，翻译抑制有两个阶段：宿主翻译的早期阻断和病毒翻译的后期抑制。我们研究了在病毒感染的这两个阶段eIF2复合物α亚基的磷酸化。在vsv感染的细胞中，磷酸化（失活）的eIF2 α直到宿主蛋白合成被抑制后才开始积累，这表明它仅在感染后阻断病毒翻译中起作用。与此一致的是，表达不可磷酸化的eIF2 α的细胞显示病毒蛋白合成时间延长，而对宿主蛋白合成抑制没有影响。在病毒感染早期，用thapsigargin诱导eIF2 α磷酸化表明病毒和宿主的翻译同样受到抑制，这表明病毒和宿主的信息对eIF2 α磷酸化同样敏感。一种表达突变基质蛋白并在抑制宿主和病毒蛋白合成方面存在缺陷的重组病毒显示eIF2 α磷酸化发生改变，表明病毒蛋白功能参与了诱导这种抗病毒反应。对eIF2 α磷酸化的分析，加上早期发现的eIF4F复合体在VSV感染期间被更早地修饰，支持翻译控制的时间/动力学模型，其中在感染后不久，eIF4F复合体的变化导致宿主蛋白合成的抑制；后来，eIF2复合体的失活阻断了VSV蛋白的合成。
In cells that allow replication of vesicular stomatitis virus (VSV), there are two phases of translation inhibition: an early block of host translation and a later inhibition of viral translation. We investigated the phosphorylation of the alpha subunit of the eIF2 complex during these two phases of viral infection. In VSV-infected cells, the accumulation of phosphorylated (inactivated) eIF2 alpha did not begin until well after host protein synthesis was inhibited, suggesting that it only plays a role in blocking viral translation later after infection. Consistent with this, cells expressing an unphosphorylatable eIF2 alpha showed prolonged viral protein synthesis without an effect on host protein synthesis inhibition. Induction of eIF2 alpha phosphorylation at early times of viral infection by treatment with thapsigargin showed that virus and host translation are similarly inhibited, demonstrating that viral and host messages are similarly sensitive to eIF2 alpha phosphorylation. A recombinant virus that expresses a mutant matrix protein and is defective in the inhibition of host and virus protein synthesis showed an altered phosphorylation of eIF2 alpha, demonstrating an involvement of viral protein function in inducing this antiviral response. This analysis of eIF2 alpha phosphorylation, coupled with earlier findings that the eIF4F complex is modified earlier during VSV infection, supports a temporal/kinetic model of translation control, where at times soon after infection, changes in the eIF4F complex result in the inhibition of host protein synthesis; at later times, inactivation of the eIF2 complex blocks VSV protein synthesis.