The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to α-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.

中文翻译：

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IDH1可微调依赖于上限的翻译起始。

代谢酶异柠檬酸脱氢酶1（IDH1）催化异柠檬酸氧化脱羧为α-酮戊二酸（α-公斤）。其突变通常导致癌症中异常的基因表达。据报道，IDH1以序列依赖的方式结合成千上万的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IDH1通过与多核糖体mRNA和翻译机制的直接关联来促进mRNA的翻译。胚胎干细胞（ESC）中的综合蛋白质组学分析显示，IDH1结合蛋白相互作用基因组中核糖体蛋白和翻译调节因子的富集显着。我们进行了核糖体分析，并分析了与主动翻译的多核糖体相关的mRNA转录本。有趣的是，ESC中IDH1的敲除导致IDH1目标中多核糖体结合mRNA的显着下调，并且起始密码子处的核糖体密度微妙上调，表示IDH1丢失后翻译启动效率低下。通过MS2-MBP系统将IDH1绑定到萤光素酶mRNA，可独立于IDH1的催化活性而促进萤光素酶翻译。有趣的是，IDH1无法增强由内部核糖体进入位点驱动的萤光素酶翻译。总之，这些结果揭示了IDH1在通过启动步骤微调帽依赖性翻译中的不可预见的作用。