Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Switzerland.
Catecholamine and Peptides Laboratory, Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Switzerland.
Nucleic Acids Res. 2021 May 21;49(9):5159-5176. doi: 10.1093/nar/gkab267.
The eIF4E are a family of initiation factors that bind the mRNA 5' cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4FS) is translationally active during stress and that it selects specific mRNA populations based on 5' TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have 'moon-lighting' functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote 'stress resistance' and adaptation.
真核翻译起始因子 4E 家族（eIF4E）是一类能与 mRNA 5' 帽结合的起始因子，调节蛋白质组和细胞表型。eIF4E1 介导整体翻译，其活性受 PI3K/AKT/mTOR 途径调控。mTOR 下调导致 eIF4E1 与 4E 结合蛋白（4EBPs）隔离成无活性复合物。第二个成员 eIF4E2 在低氧条件下调节转录组。然而，第三个成员 eIF4E3 的确切功能仍然难以捉摸。我们使用一系列技术对其功能进行了剖析。从它不与 4EBP1 相互作用的观察出发，我们证明当 Torin1 抑制 mTOR 途径时，eIF4E3 会被招募到 eIF4F 复合物中。核糖体测序研究表明，该复合物（eIF4FS）在应激时具有翻译活性，并且根据 5' TL（UTR）长度选择特定的 mRNA 群体。相互作用组揭示它与细胞蛋白结合，而不仅仅是与起始因子结合，这表明它可能具有“月光”功能。最后，我们提供的证据表明，在 eIF4E3 KO 背景下，细胞代谢发生改变，但仅在 Torin1 处理时才会发生改变。我们提出，eIF4E3 作为整合应激反应的第二分支，重新编程转录组以促进“应激抵抗”和适应。
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