Role of the Akt pathway in mRNA translation of interferon-stimulated genes.
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.
Kaur
Surinder
S
Division of Hematology-Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School and Lakeside Veterans Affairs Medical Center, Chicago, IL 60611, USA.
Sassano
Antonella
A
Dolniak
Blazej
B
Joshi
Sonali
S
Majchrzak-Kita
Beata
B
Baker
Darren P
DP
Hay
Nissim
N
Fish
Eleanor N
EN
Platanias
Leonidas C
LC
D000818:Animals; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004686:Encephalomyocarditis virus / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic / Q000187:drug effects; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D016207:Cytokines; C489550:G1p2 protein, mouse; D016898:Interferon-alpha; D050791:STAT Transcription Factors; D014452:Ubiquitins; D007371:Interferon-gamma; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases