Colina Rodney, Costa-Mattioli Mauro, Dowling Ryan J O, Jaramillo Maritza, Tai Lee-Hwa, Breitbach Caroline J, Martineau Yvan, Larsson Ola, Rong Liwei, Svitkin Yuri V, Makrigiannis Andrew P, Bell John C, Sonenberg Nahum
Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Nature. 2008 Mar 20;452(7185):323-8. doi: 10.1038/nature06730. Epub 2008 Feb 13.
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- 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.
细胞因子的转录激活，如I型干扰素（干扰素（IFN）-α和IFN-β），构成了抗病毒防御的第一道防线。在此我们表明，翻译控制对于I型干扰素产生的诱导至关重要。在缺乏翻译抑制因子4E-BP1和4E-BP2的小鼠胚胎成纤维细胞中，引发I型干扰素产生的阈值降低。因此，脑心肌炎病毒、水疱性口炎病毒、流感病毒和辛德毕斯病毒的复制受到显著抑制。此外，4E-和4E-BP2基因（分别也称为Eif4ebp1和Eif4ebp2）均被敲除的小鼠对水疱性口炎病毒感染具有抗性，这与浆细胞样树突状细胞中I型干扰素产生的增强以及肺中干扰素调节基因的表达相关。4E-BP1-/- 4E-BP2-/-双敲除小鼠胚胎成纤维细胞中I型干扰素反应的增强是由干扰素调节因子7（Irf7）信使核糖核酸翻译的上调引起的。这些发现突出了4E-BP作为I型干扰素产生的负调节因子的作用，其通过对Irf7 mRNA的翻译抑制来实现。
