IDH1 fine-tunes cap-dependent translation initiation.
IDH1 fine-tunes cap-dependent translation initiation.
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IDH1 微调帽依赖性翻译起始。
DOI：
10.1093/jmcb/mjz082
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Shen Xiaohua
中科院分区：
文献类型：
--
作者：
Liu Lichao;Lu J Yuyang;Li Fajin;Xing Xudong;Li Tong;Yang Xuerui;Shen Xiaohua
代谢酶异柠檬酸脱氢酶1（IDH 1）催化异柠檬酸氧化脱羧为α-酮戊二酸（α-KG）。它的突变常常导致癌症中的异常基因表达。据报道IDH 1以序列依赖性方式结合数千种RNA转录物;然而，这种RNA结合活性的功能意义仍然难以捉摸。在这里，我们报告IDH 1促进mRNA翻译通过直接协会与多核糖体mRNA和翻译机器。在胚胎干细胞（ESC）的全面蛋白质组学分析显示显着丰富的核糖体蛋白和翻译调节IDH 1结合的蛋白质相互作用。我们进行了核糖体分析，并分析了与积极翻译多核糖体相关的mRNA转录本。有趣的是，敲除ESC中的IDH 1导致IDH 1靶标中多核糖体结合mRNA的显著下调和起始密码子处核糖体密度的微妙上调，表明IDH 1丢失后翻译起始效率低下。通过MS 2-MBP系统将IDH 1拴系到荧光素酶mRNA促进荧光素酶翻译，而与IDH 1的催化活性无关。有趣的是，IDH 1不能增强由内部核糖体进入位点驱动的荧光素酶翻译。总之，这些结果揭示了IDH 1在通过起始步骤微调帽依赖性翻译中的不可预见的作用。
The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate toα-ketoglutarate (α-KG). Its mutation often leads to aberrant gene expression in cancer. IDH1 was reported to bind thousands of RNA transcripts in a sequence-dependent manner; yet, the functional significance of this RNA-binding activity remains elusive. Here, we report that IDH1 promotes mRNA translation via direct associations with polysome mRNA and translation machinery. Comprehensive proteomic analysis in embryonic stem cells (ESCs) revealed striking enrichment of ribosomal proteins and translation regulators in IDH1-bound protein interactomes. We performed ribosomal profiling and analyzed mRNA transcripts that are associated with actively translating polysomes. Interestingly, knockout of IDH1 in ESCs led to significant downregulation of polysome-bound mRNA in IDH1 targets and subtle upregulation of ribosome densities at the start codon, indicating inefficient translation initiation upon loss of IDH1. Tethering IDH1 to a luciferase mRNA via the MS2-MBP system promotes luciferase translation, independently of the catalytic activity of IDH1. Intriguingly, IDH1 fails to enhance luciferase translation driven by an internal ribosome entry site. Together, these results reveal an unforeseen role of IDH1 in fine-tuning cap-dependent translation via the initiation step.