Role of the At pathway in mRNA translation of interferon-stimulated genes
Role of the At pathway in mRNA translation of interferon-stimulated genes
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DOI：
10.1073/pnas.0710907105
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发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Platanias, Leonidas C.
中科院分区：
文献类型：
--
作者：
Kaur, Surinder;Sassano, Antonella;Platanias, Leonidas C.
I型和II型IFN受体参与了多种信号传导途径，但它们在IFN介导的生物反应中的具体作用和可能的协调仍然未知。我们提供的证据表明，Akt激酶的激活是IFN诱导的mTOR/p70 S6激酶通路的参与所必需的。我们的数据证实Akt活性对于上调关键的IFN-α和IFN-γ诱导蛋白是必不可少的，这些蛋白在IFN应答的诱导中具有重要的功能性后果。Akt途径的这种作用与IFN依赖性STAT磷酸化/激活或转录调节的调节活性无关。相比之下，它们反映了通过直接控制mTOR途径对mRNA翻译的调节活性。在使用Akt 1和Akt 2双敲除细胞的研究中，我们发现Akt激酶的缺失导致IFN诱导的抗病毒应答显著降低，从而确立了At途径在IFN信号传导中的关键作用。因此，通过IFN受体激活Akt途径补充了IFN激活的JAK-STAT途径的功能，允许IFN刺激的基因的mRNA翻译，并最终诱导IFN的生物学效应。
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 At 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 IFNI-stimulated genes and, ultimately, the induction of the biological effects of IFNs.