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IDH1 fine-tunes cap-dependent translation initiation
Lichao Liu1, J. Yuyang Lu1, Fajin Li2, Xudong Xing3, Tong Li1, Xuerui Yang2, and Xiaohua Shen 1,*
1 Tsinghua–Peking Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
2 MOE Key Laboratory of Bioinformatics, Center for Synthetic & Systems Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
3 Peking University–Tsinghua University–National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing 100084, China
*Correspondence to:Xiaohua Shen, E-mail: xshen@tsinghua.edu.cn
J Mol Cell Biol, Volume 11, Issue 10, October 2019, Pages 816-828  https://doi.org/10.1093/jmcb/mjz082
Keyword: IDH1, proteomic interactome, translation regulation, RNA-binding protein
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.