Translational control of the innate immune response through IRF-7

Rodney Colina, Mauro Costa-Mattioli, et al. 2008. Nature. 452, 323-328

Speaker: Yi Chun Chen (陳逸純)                                           Time: 14:00~15:00, Apr 9, 2008

Commentator: Dr. Cheng-Chan Lu (呂政展教授)          Place: Room 601

Abstract:

Transcriptional activation of cytokines, such as type-I interferon (interferon (IFN)-a and IFN-b), constitutes the first line of antiviral defense. In this article, the authors discovered a critical translational control for inducing of type-I IFN production. In mouse embryonic fibroblasts (MEFs) lacking the translational repressors 4E-BP1 and 4E-BP2, the threshold for eliciting type-I IFN production is reduced. After infected with encephalomyocarditis virus, vesicular stomatitis virus (VSV), influenza virus or Sindbis virus, they found that the productions of type-I IFN were markedly suppressed more in wide-type MEFs than in 4E-BP1^-/- 4E-BP2^-/- double knockout MEFs. In order to realize the downregulation of type I IFN production, they treated MEFs with poly(I:C), a synthetic double-stranded RNA (dsRNA) that is a potent inducer of type-I IFN, and proofed that the lack of 4E-BPs results in enhanced type-I IFN production. Moreover, double knockout mice were resistant to VSV infection, and this correlated with an enhanced type-I IFN production in plasmacytoid dendritic cells and the expression of IFN-regulated genes in the lungs. To determine the molecular mechanism by which type-I IFN production was enhanced in double knockout cell or mice, they found interferon regulatory factor 7 (Irf7) mRNA was the highest ranked gene by gene expression microarrays. Furthermore, they found Irf7 mRNA was translated more efficiently by using sucrose density gradient RT-PCR, and western blotting. These findings highlight the role of 4E-BPs as negative regulators of type-I IFN production, via translational repression of Irf7 mRNA.

References:

1.     Le Bacquer, O., et al. 2007. Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E–BP1 and 4E–BP2. J. Clin. Invest. 117, 387–396.

2.     Honda, K., et al. 2005. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 434, 772–777.