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PNAS 105 (12): 4808-4813

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / IMMUNOLOGY

Role of the Akt pathway in mRNA translation of interferon-stimulated genes

Surinder Kaur*, Antonella Sassano*, Blazej Dolniak*, Sonali Joshi*, Beata Majchrzak-Kita{dagger}, Darren P. Baker{ddagger}, Nissim Hay§, Eleanor N. Fish{dagger}, and Leonidas C. Platanias*,¶

*Division of Hematology–Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, IL 60611; {dagger}Division of Cell and Molecular Biology, University Health Network and Department of Immunology, Toronto Research Institute, University of Toronto, Toronto, ON, Canada M5G 2M1; {ddagger}Biogen Idec, Inc., 14 Cambridge Center, Cambridge, MA 02142; and §Department of Molecular Genetics, University of Illinois, Chicago, IL 60607

Edited by George R. Stark, Cleveland Clinic Foundation, Cleveland, OH, and approved January 25, 2008

Received for publication November 16, 2007.

Abstract: Multiple signaling pathways are engaged by the type I and II IFN receptors, but their specific roles and possible coordination in the generation of IFN-mediated biological responses remain unknown. We provide evidence that activation of Akt kinases is required for IFN-inducible engagement of the mTOR/p70 S6 kinase pathway. Our data establish that Akt activity is essential for up-regulation of key IFN-{alpha}- and IFN-{gamma}-inducible proteins, which have important functional consequences in the induction of IFN responses. Such effects of the Akt pathway are unrelated to regulatory activities on IFN-dependent STAT phosphorylation/activation or transcriptional regulation. By contrast, they reflect regulatory activities on mRNA translation via direct control of the mTOR pathway. In studies using Akt1 and Akt2 double knockout cells, we found that the absence of Akt kinases results in dramatic reduction in IFN-induced antiviral responses, establishing a critical role of the Akt pathway in IFN signaling. Thus, activation of the Akt pathway by the IFN receptors complements the function of IFN-activated JAK–STAT pathways, by allowing mRNA translation of IFN-stimulated genes and, ultimately, the induction of the biological effects of IFNs.

Author contributions: E.N.F. and L.C.P. designed research; S.K., A.S., B.D., S.J., and B.M.-K. performed research; D.P.B. and N.H. contributed new reagents/analytic tools; S.K., E.N.F., and L.C.P. analyzed data; and S.K. and L.C.P. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0710907105/DC1.

To whom correspondence should be addressed. E-mail: l-platanias{at}northwestern.edu

© 2008 by The National Academy of Sciences of the USA

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