Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses
Antiviral effect of the mammalian translation initiation factor 2α kinase GCN2 against RNA viruses
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DOI：
10.1038/sj.emboj.7601073
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发表时间：
2006-04-19
期刊：
影响因子：
11.4
通讯作者：
de Haro, Cesar
中科院分区：
文献类型：
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作者：
Berlanga, Juan J.;Ventoso, Ivan;de Haro, Cesar
在哺乳动物中，四种不同的蛋白激酶：血红素调节抑制剂、双链 RNA 依赖性蛋白激酶 (PKR)、一般控制非去阻抑蛋白 2 (GCN2) 和 PKR 样内质网激酶，通过磷酸化起始因子 2 (eIF2 α) 的 α 亚基来调节蛋白质合成，以响应环境应激。我们现在报道，哺乳动物 GCN2 在辛德毕斯病毒 (SV) 基因组 RNA 的两个不相邻区域与其组氨酰-tRNA 合成酶相关结构域结合后在体外被特异性激活。此外，内源性 GCN2 在 SV 感染后在细胞中被激活。引人注目的是，源自 GCN2(-/-) 小鼠的成纤维细胞对 SV 或水泡性口炎病毒感染的耐受性增加。我们进一步表明，缺乏 GCN2 的小鼠极易受到鼻内 SV 感染，与类似感染的对照动物相比，其大脑中的病毒滴度较高。 NIH 3T3 细胞中野生型 GCN2 的过度表达（而非催化失活的 GCN2-K618R 变体）损害了许多 RNA 病毒的复制。我们确定 GCN2 通过阻断基因组 SV RNA 的早期病毒翻译来抑制 SV 复制。这些发现表明，GCN2 作为细胞对 RNA 病毒反应的早期介质，发挥着迄今为止未被认识的作用。
In mammals, four different protein kinases, heme-regulated inhibitor, double-stranded RNA-dependent protein kinase (PKR), general control non-derepressible-2 (GCN2) and PKR-like endoplasmic reticulum kinase, regulate protein synthesis in response to environmental stresses by phosphorylating the alpha-subunit of the initiation factor 2 (eIF2 alpha). We now report that mammalian GCN2 is specifically activated in vitro upon binding of two nonadjacent regions of the Sindbis virus (SV) genomic RNA to its histidyl-tRNA synthetase-related domain. Moreover, endogenous GCN2 is activated in cells upon SV infection. Strikingly, fibroblasts derived from GCN2(-/-) mice possess an increased permissiveness to SV or vesicular stomatitis virus infection. We further show that mice lacking GCN2 are extremely susceptible to intranasal SV infection, demonstrating high virus titers in the brain compared to similarly infected control animals. The overexpression of wild-type GCN2, but not the catalytically inactive GCN2-K618R variant, in NIH 3T3 cells impaired the replication of a number of RNA viruses. We determined that GCN2 inhibits SV replication by blocking early viral translation of genomic SV RNA. These findings point to a hitherto unrecognized role of GCN2 as an early mediator in the cellular response to RNA viruses.