title: Possible role of phosphoinositide-3-kinase in Mx1 protein translation and antiviral activity of interferon-omega-stimulated HeLa cells.
abstract: Interferon ω (IFN-ω), a cytokine released during innate immune activation, is well known for promoting direct antiviral responses; however, the possible signal pathways that are initiated by IFN-ω binding to the type I IFN receptors have not been fully studied. Here, we provide evidence that activation of phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling plays a pivotal role in the generation of IFN-ω-mediated biological responses. We found that LY294002 (PI3K inhibitor)-attenuated antiviral activities are induced by IFN-ω treatment. Although such effects of LY294002 are unrelated to regulatory activities on IFN-ω-dependent Mx1 (myxovirus resistance 1) or Mx2 gene transcriptional regulation, translation of Mx1 protein, which was known as a key mediator of cell-autonomous antiviral resistance, was significantly reduced by PI3K inhibition. Further studies showed that PI3K inhibition using LY294002 leads to a decrease in PI3K substrate Akt and mitogen-activated protein kinase extracellular signal-regulated kinase and p38 phosphorylation/activation. In addition, although LY294002 was not able to reduce STAT1 activation, we found that the mammalian target of rapamycin (mTOR)/p70 S6 kinase pathway was significantly attenuated by inhibition of the PI3K/Akt signaling pathway. These results indicate that the PI3K/Akt pathway is a common and central integrator for antiviral responses in IFN-ω signaling via its regulatory effects on mTOR that are required for initiation of mRNA translation of Mx genes.
authors: Advanced Therapy Products Research Division, National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration, Chungcheongbuk-do, Republic of Korea.
authors: Youngjun
authors: Y
authors: Seo
authors: Mihee
authors: M
authors: Kim
authors: Minjoung
authors: M
authors: Choi
authors: Sunhee
authors: S
authors: Kim
authors: Kidae
authors: K
authors: Park
authors: Ilung
authors: I
authors: Oh
authors: Seungtae
authors: S
authors: Chung
authors: Hongwon
authors: H
authors: Suh
authors: Seunghwa
authors: S
authors: Hong
authors: Suenie
authors: S
authors: Park
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004686:Encephalomyocarditis virus / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D064547:Myxovirus Resistance Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014176:Protein Biosynthesis; D014709:Vero Cells; D018116:Vesiculovirus / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D019204:GTP-Binding Proteins; D007370:Interferon Type I; D064547:Myxovirus Resistance Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C063743:interferon omega 1