RNA Systems Biochemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Japan.
Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan.
Nat Struct Mol Biol. 2024 Oct;31(10):1557-1566. doi: 10.1038/s41594-024-01321-7. Epub 2024 May 21.
Eukaryotic translation initiation factor (eIF)4A-a DEAD-box RNA-binding protein-plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the interaction between TOP mRNAs and LARP1 and, thus, ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.
真核翻译起始因子（eIF）4A-a 是一种 DEAD 框 RNA 结合蛋白，在翻译起始中发挥着重要作用。最近的报告表明，eIF4A 具有依赖解旋酶和不依赖解旋酶的功能，但 eIF4A 的多方面功能尚未得到充分探索。在这里，我们表明 eIF4A1 增强了机械靶标雷帕霉素复合物 1（mTORC1）抑制期间的翻译抑制，mTORC1 是控制细胞增殖的必需激酶复合物。RNA 下拉测序显示，eIF4A1 优先结合含有末端寡嘧啶（TOP）基序的 mRNA，mTORC1 抑制后其翻译迅速受到抑制。这种选择性相互作用依赖于 La 相关 RNA 结合蛋白 LARP1。核糖体谱分析显示，EIF4A1 的缺失减弱了 mTORC1 失活时 TOP mRNA 的翻译抑制。此外，eIF4A1 增加了 TOP mRNA 和 LARP1 之间的相互作用，从而确保在 mTORC1 抑制时更强的翻译抑制。我们的数据表明，eIF4A1 通过抑制性结合伴侣在调节蛋白质合成方面具有多效性，并提供了通用翻译激活因子的抑制作用的独特示例。
