eIF2α Phosphorylation Mediates IL24-Induced Apoptosis through Inhibition of Translation.
eIF2α Phosphorylation Mediates IL24-Induced Apoptosis through Inhibition of Translation.
复制标题
DOI：
10.1158/1541-7786.mcr-16-0454
复制
发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Sauane M
中科院分区：
文献类型：
--
作者：
Persaud L;Zhong X;Alvarado G;Do W;Dejoie J;Zybtseva A;Aktas BH;Sauane M
白细胞介素24（IL 24）是一种免疫调节细胞因子，也显示出广泛的癌症特异性抑制作用。IL-24的肿瘤抑制活性包括抑制血管生成、对化疗增敏和癌症特异性细胞凋亡。翻译起始因子的超生理活化和/或过表达涉及癌症动物模型以及人类癌症亚组的起始和进展。翻译起始因子的激活和/或过表达与癌症的侵袭性和不良预后相关。两种限速翻译起始复合物，三元复合物和eIF 4F复合物分别受eIF 2 α和4 E-BP 1磷酸化的调节。本文报道的工作提供了直接证据，表明IL-24诱导抑制翻译起始，导致鳞状细胞癌细胞凋亡。使用eIF 2 α的显性组成型活性突变体（其对磷酸化具有抗性）来确定eIF 2 α在IL 24诱导的细胞凋亡中的参与。用IL-24处理导致蛋白质合成的抑制、三元复合物消耗的下游生物标志物（如CHOP）的表达以及癌细胞中细胞凋亡的诱导。eIF 2 α的组成型活性非磷酸化突变体eIF 2 α-S51 A逆转了IL 24介导的翻译阻断和IL 24诱导的细胞凋亡。有趣的是，IL-24处理还引起以高亲和力结合eIF 4 E的4 E-BP 1的低磷酸化，从而阻止其与eIF 4G结合，并因此阻止eIF 4F复合物组装。这些结果表明，IL-24在抑制翻译中的作用是以前未认识到的，通过eIF 2 α的磷酸化和4 E-BP 1的去磷酸化介导的，并为IL-24对基因特异性表达的翻译控制提供了第一个直接证据。
Interleukin 24 (IL24) is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. Supra-physiologic activation and/or overexpression of translation initiation factors are implicated in the initiation and progression of cancer animal models as well as a subset of human cancers. Activation and/or overexpression of translation initiation factors correlate with aggressiveness of cancer and poor prognosis. Two rate-limiting translation initiation complexes, the ternary complex and the eIF4F complex are regulated by eIF2α and 4E-BP1 phosphorylation, respectively. The work reported here provides direct evidence that IL-24 induces inhibition of translation initiation leading to apoptosis in squamous cell carcinoma. A dominant constitutively active mutant of eIF2α, which is resistant to phosphorylation, was used to determine the involvement of eIF2α in IL24-induced apoptosis. Treatment with IL-24 resulted in inhibition of protein synthesis, expression of downstream biomarkers of ternary complex depletion such as CHOP, and induction of apoptosis in cancer cells. The constitutively active non-phosphorylatable mutant of eIF2α, eIF2α-S51A, reversed both the IL24-mediated translational block and IL24-induced apoptosis. Intriguingly, IL-24 treatment also caused hypophosphorylation of 4E-BP1 which binds to eIF4E with high-affinity thus preventing its association with eIF4G and therefore preventing elF4F complex assembly. These results demonstrate a previously unrecognized role of IL-24 in inhibition of translation, mediated through both phosphorylation of eIF2α and de-phosphorylation of 4E-BP1, and provide the first direct evidence for translation control of gene-specific expression by IL-24.