Interferons (IFNs), including the type I IFN-α and IFN-β and the type II IFN-γ, signal through a well-characterized pathway involving the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) to stimulate genes involved in inflammatory and antiviral responses. Previous reports had suggested that IFNs can also signal through the kinase Akt, but the effect of signaling through this pathway has been controversial. Kaur et al. add to this story by providing evidence that Akt signaling connects both type I and type II IFN signaling to regulation of translation through the mTOR pathway. By comparing wild-type mouse embryo fibroblasts (MEFs) with those in which both Akt1 and Akt2 were knocked out, the authors showed that Akt activation (phosphorylation) occurred in response to IFNs. Furthermore, phosphorylation and activation of the kinase p70S6K in response to IFNs was impaired in the Akt double-knockout MEFs, as was the phosphorylation of the translational repressor 4E-BP1. The abundance of ISG15, which is encoded by a gene stimulated by type I IFN signaling, and CXCL10, which is encoded by a gene stimulated by type II IFN signaling, was decreased in the Akt double-knockout MEFs. This was not due to impaired JAK/STAT signaling, because the transcripts were elevated; instead, this appeared to be due to inhibition of translation in the Akt double-knockout cells. This interpretation was supported by analysis of the amount of Isg15 mRNA in the polysomal fraction in response to IFN-α, which was decreased in the Akt double-knockout MEFs. Finally, the importance of this Akt-mediated regulation of translation for antiviral response was demonstrated by challenging wild-type and double-knockout cells with encephalomyocarditis virus and showing that IFN-α did not protect the knockout cells from the cytopathic effects of the virus as effectively as it did the wild-type cells.
S. Kaur, A. Sassano, B. Dolniak, S. Joshi, B. Majchrzak-Kita, D. P. Baker, N. Hay, E. N. Fish, L. C. Platanias, Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc. Natl. Acad. Sci. U.S.A. 105, 4808-4813 (2008). [Abstract] [Full Text]