Translational control of the innate immune response through IRF-7
Translational control of the innate immune response through IRF-7
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DOI：
10.1038/nature06730
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发表时间：
2008-03-20
期刊：
影响因子：
64.8
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Colina, Rodney;Costa-Mattioli, Mauro;Sonenberg, Nahum
细胞因子如I型干扰素（干扰素（IFN）-α和IFN-β）的转录激活构成抗病毒防御的第一道防线。在这里，我们表明，翻译控制是至关重要的诱导I型干扰素的生产。在缺乏翻译阻遏物4 E-BP 1和4 E-BP 2的小鼠胚胎成纤维细胞中，诱导I型IFN产生的阈值降低。因此，脑心肌炎病毒、水泡性口炎病毒、流感病毒和辛德毕斯病毒的复制被显著抑制。此外，敲除4 E-BP 1和4 E-BP 2基因（也分别称为Eif 4 ebp 1和Eif 4 ebp 2）的小鼠对水泡性口炎病毒感染具有抗性，这与浆细胞样树突细胞中I型IFN产生的增强和肺中IFN调节基因的表达相关.在4 E-BP 1（-/-）4 E-BP 2（-/-）双敲除小鼠胚胎成纤维细胞中增强的I型IFN应答是由干扰素调节因子7（Irf 7）信使RNA翻译的上调引起的。这些发现强调了4 E-BP作为I型IFN产生的负调节剂的作用，通过Irf 7 mRNA的翻译抑制.
Transcriptional activation of cytokines, such as type-I interferons ( interferon ( IFN)- alpha and IFN- beta), constitutes the first line of antiviral defence. Here we show that translational control is critical for induction of type- I IFN production. In mouse embryonic fibroblasts lacking the translational repressors 4E- BP1 and 4E- BP2, the threshold for eliciting type- I IFN production is lowered. Consequently, replication of encephalomyocarditis virus, vesicular stomatitis virus, influenza virus and Sindbis virus is markedly suppressed. Furthermore, mice with both 4E- BP1 and 4E- BP2 genes ( also known as Eif4ebp1 and Eif4ebp2, respectively) knocked out are resistant to vesicular stomatitis virus infection, and this correlates with an enhanced type- I IFN production in plasmacytoid dendritic cells and the expression of IFN- regulated genes in the lungs. The enhanced type- I IFN response in 4E-BP1(-/-) 4E-BP2(-/-) double knockout mouse embryonic fibroblasts is caused by upregulation of interferon regulatory factor 7 ( Irf7) messenger RNA translation. These findings highlight the role of 4E- BPs as negative regulators of type- I IFN production, via translational repression of Irf7 mRNA.