Division of Hematology-Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University Medical School and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60611, USA.
J Biol Chem. 2011 Jan 14;286(2):1147-56. doi: 10.1074/jbc.M110.183566. Epub 2010 Nov 12.
Although the mechanisms of generation of signals that control transcriptional activation of Type III IFN (IFNλ)-regulated genes have been identified, very little is known about the mechanisms by which the IFNλ receptor generates signals for mRNA translation of IFNλ-activated genes. We provide evidence that IFNλ activates the p90 ribosomal protein S6 kinase 1 (RSK1) and its downstream effector, initiation factor eIF4B. Prior to its engagement by the IFNλ receptor, the non-active form of RSK1 is present in a complex with the translational repressor 4E-BP1 in IFNλ-sensitive cells. IFNλ-inducible phosphorylation/activation of RSK1 results in its dissociation from 4E-BP1 at the same time that 4E-BP1 dissociates from eIF4E to allow formation of eIF4F and initiation of cap-dependent translation. Our studies demonstrate that such IFNλ-dependent engagement of RSK1 is essential for up-regulation of p21(WAF1/CIP1) expression, suggesting a mechanism for generation of growth-inhibitory responses. Altogether, our data provide evidence for a critical role for the activated RSK1 in IFNλ signaling.
虽然已经确定了控制 III 型干扰素（IFNλ）调节基因转录激活的信号产生机制，但对于 IFNλ 受体产生信号以翻译 IFNλ 激活基因的机制知之甚少。我们提供的证据表明，IFNλ 激活了 p90 核糖体蛋白 S6 激酶 1（RSK1）及其下游效应因子起始因子 eIF4B。在与 IFNλ 受体结合之前，非活性形式的 RSK1 存在于 IFNλ 敏感细胞中与翻译抑制剂 4E-BP1 形成的复合物中。IFNλ 诱导的 RSK1 磷酸化/激活导致其与 4E-BP1 分离，同时 4E-BP1 与 eIF4E 分离，以允许形成 eIF4F 并启动帽依赖性翻译。我们的研究表明，RSK1 的这种 IFNλ 依赖性结合对于上调 p21（WAF1/CIP1）的表达是必不可少的，这表明了产生生长抑制反应的一种机制。总之，我们的数据为激活的 RSK1 在 IFNλ 信号转导中的关键作用提供了证据。
