Regulation of host translational machinery by African swine fever virus.
Regulation of host translational machinery by African swine fever virus.
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DOI：
10.1371/journal.ppat.1000562
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发表时间：
2009-08
期刊：
影响因子：
6.7
通讯作者：
Revilla Y
中科院分区：
文献类型：
--
作者：
Castelló A;Quintas A;Sánchez EG;Sabina P;Nogal M;Carrasco L;Revilla Y
非洲猪瘟病毒（ASFV）与其他复杂的DNA病毒一样，采用多种策略来逃避宿主的防御系统，如炎症和免疫反应以及细胞死亡。在这里，我们分析了ASFV诱导的翻译机制的修改。在ASFV感染期间，eIF 4G和eIF 4 E被磷酸化（分别为Ser 1108和Ser 209），而4 E-BP 1在感染后早期被过度磷酸化，并在18 h后被低磷酸化。事实上，在ASFV感染的细胞中观察到eIF 4F组装的有效增加，这是通过雷帕霉素处理来阻止的。eIF 4 E、eIF 4GI和4 E-BP 1的磷酸化对于增强病毒蛋白质产生是重要的，但对于ASFV感染不是必需的，如在雷帕霉素或CGP 57380处理的细胞中观察到的。然而，eIF 4F组分对于ASFV蛋白合成和病毒传播是必不可少的，因为COS-7或Vero细胞中eIF 4 E或eIF 4G的缺失强烈阻止了病毒蛋白的积累并降低了病毒滴度。此外，eIF 4F不仅被激活，而且在感染早期在病毒工厂内重新分布，而eIF 4G和eIF 4 E在晚期围绕这些区域。事实上，翻译机制的其他组分如eIF 2 α、eIF 3b、eIF 4 E、eEF 2和核糖体P蛋白在ASFV工厂周围的区域富集。值得注意的是，线粒体网络在ASFV感染的细胞中与核糖体共定位。因此，翻译和ATP合成似乎是耦合和划分在病毒工厂的外围。在ASFV感染后的后期，多腺苷酸化的mRNA从Vero细胞的细胞质中消失，除了在病毒工厂内。这些mRNA库的分布类似于病毒晚期mRNA的定位。因此，细胞多聚腺苷酸化mRNA的降解和翻译机制向病毒工厂的募集可能有助于抑制宿主蛋白质合成，促进感染细胞中ASFV蛋白质的产生。非洲猪瘟病毒（ASFV）是一种大型DNA病毒，感染不同种类的猪，引起急性，高度传染性和往往致命的疾病。ASFV感染的特征在于缺乏中和免疫应答，这迄今阻碍了常规疫苗的开发。虽然许多报道关注ASFV基因和调节细胞程序性死亡和免疫逃避的机制，但迄今为止还不知道ASFV如何在感染的细胞中复制。作为细胞内寄生物，病毒高度依赖宿主翻译机器来合成其自身蛋白质。我们已经观察到，在ASFV感染期间，细胞蛋白质合成被强烈抑制，而病毒蛋白质被有效地产生。此外，我们在这里描述了ASFV激活和重新分配细胞机器以合成其自身蛋白质的过程。据报道，ASFV在称为工厂的离散细胞质区域内复制。在这方面，我们已经确定了重要的细胞因子参与控制蛋白质的合成，位于靠近病毒工厂，与核糖体和线粒体网络，这代表了一个复杂的病毒控制机制。
African swine fever virus (ASFV), like other complex DNA viruses, deploys a variety of strategies to evade the host's defence systems, such as inflammatory and immune responses and cell death. Here, we analyse the modifications in the translational machinery induced by ASFV. During ASFV infection, eIF4G and eIF4E are phosphorylated (Ser1108 and Ser209, respectively), whereas 4E-BP1 is hyperphosphorylated at early times post infection and hypophosphorylated after 18 h. Indeed, a potent increase in eIF4F assembly is observed in ASFV-infected cells, which is prevented by rapamycin treatment. Phosphorylation of eIF4E, eIF4GI and 4E-BP1 is important to enhance viral protein production, but is not essential for ASFV infection as observed in rapamycin- or CGP57380-treated cells. Nevertheless, eIF4F components are indispensable for ASFV protein synthesis and virus spread, since eIF4E or eIF4G depletion in COS-7 or Vero cells strongly prevents accumulation of viral proteins and decreases virus titre. In addition, eIF4F is not only activated but also redistributed within the viral factories at early times of infection, while eIF4G and eIF4E are surrounding these areas at late times. In fact, other components of translational machinery such as eIF2α, eIF3b, eIF4E, eEF2 and ribosomal P protein are enriched in areas surrounding ASFV factories. Notably, the mitochondrial network is polarized in ASFV-infected cells co-localizing with ribosomes. Thus, translation and ATP synthesis seem to be coupled and compartmentalized at the periphery of viral factories. At later times after ASFV infection, polyadenylated mRNAs disappear from the cytoplasm of Vero cells, except within the viral factories. The distribution of these pools of mRNAs is similar to the localization of viral late mRNAs. Therefore, degradation of cellular polyadenylated mRNAs and recruitment of the translation machinery to viral factories may contribute to the inhibition of host protein synthesis, facilitating ASFV protein production in infected cells. African Swine Fever Virus (ASFV) is a large DNA virus that infects different species of swine, causing an acute, highly contagious and often fatal disease. Infection by ASFV is characterized by the absence of a neutralizing immune response, which has so far hampered the development of a conventional vaccine. While a number of reports have been concerned with ASFV genes and mechanisms regulating programmed cell death and immune evasion, nothing is known so far regarding how ASFV replicates in the infected cells. As intracellular parasites, viruses are highly dependent on host translation machinery for synthesizing their own proteins. We have observed that the cellular protein synthesis is strongly inhibited during ASFV infection, while viral proteins are efficiently produced. Furthermore, we here describe the processes by which ASFV activates and redistributes the cellular machinery to synthesize its own proteins. It has been reported that ASFV replicates within discrete cytoplasmic areas known as factories. In this regard, we have identified the presence of important cellular factors involved in the control of protein synthesis, located close to viral factories, together with ribosomes and the mitochondrial network, which represents a sophisticated mechanism of viral control.
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DOI：
10.1006/bbrc.1995.2553
发表时间：
1995-10-24
影响因子：
3.1
作者：
ALDABE, R;FEDUCHI, E;CARRASCO, L
通讯作者：
CARRASCO, L
影响因子：
3.4
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
Lyles, DS
影响因子：
4.4
作者：
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通讯作者：
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