Translational control of the innate immune response through IRF-7

• Published in: Nature Vol. 452; no. 7185; pp. 323 - 328
• Main Authors: Jaramillo, Maritza, Rong, Liwei, Martineau, Yvan, Costa-Mattioli, Mauro, Svitkin, Yuri V, Tai, Lee-Hwa, Sonenberg, Nahum, Bell, John C, Colina, Rodney, Breitbach, Caroline J, Makrigiannis, Andrew P, Dowling, Ryan J. O, Larsson, Ola
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.03.2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Dendritic Cells - immunology; Embryo, Mammalian - cytology; Encephalomyocarditis virus; Eukaryotic Initiation Factors - deficiency; Eukaryotic Initiation Factors - genetics; Eukaryotic Initiation Factors - metabolism; Fibroblasts - virology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Deletion; Gene expression; Genetic aspects; Genetic translation; Genetics of the immune response; Humanities and Social Sciences; Immune response; Immunity, Innate - genetics; Immunity, Innate - immunology; Immunobiology; Immunology; Influenza virus; Interferon; Interferon Regulatory Factor-7 - biosynthesis; Interferon Regulatory Factor-7 - genetics; Interferon Regulatory Factor-7 - metabolism; Interferon Type I - biosynthesis; Interferon Type I - immunology; Medicin och hälsovetenskap; Mice; Mice, Knockout; Molecular biology; multidisciplinary; Phosphoproteins - deficiency; Phosphoproteins - genetics; Phosphoproteins - metabolism; Physiological aspects; Protein Biosynthesis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Science; Science (multidisciplinary); Sindbis virus; Vesicular stomatitis Indiana virus - physiology; Vesicular stomatitis virus; Virus Physiological Phenomena; Virus Replication; Viruses; Canada; Binding protein; Regulation(control); Immune response; Initiation factor eIF4E; Natural immunity; Repression; Genetic translation
• ISSN: 0028-0836; 1476-4687; 1476-4687; 1476-4679
• DOI: 10.1038/nature06730

Transcriptional activation of cytokines, such as type-I interferons (interferon (IFN)-α and IFN-β), 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. Found in translation Transcriptional control of interferon-mediated gene expression plays a major role in the activation of the innate immune response, but little is known about the role of translational control — the control exerted at the stage at which mRNA is converted into a protein. Colina et al . show that in mice lacking the translational repressors 4E-BP1 and 4E-BP2, the threshold for eliciting type-I interferon in response to challenge by various viruses is lowered and virus replication is dramatically suppressed. The 4E-BP repressors appear to act by the synthesis of the protein IRF-7, the master regulator of interferon production. By targeting 4E-BP1 and 4E-BP2 with drugs, it may be possible to boost innate immunity against virus infection. Production of type-I interferon is regulated by the transcription factor IRF-7. This paper shows that IRF-7 is negatively regulated by translational repressor proteins 4E-BP1 and 4E-BP2. Viral infection promotes mTOR-mediated phosphorylation of the repressor proteins and allows type-I interferon production to proceed.