eIF4A1-dependent mRNAs employ purine-rich 5'UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation.
eIF4A1-dependent mRNAs employ purine-rich 5'UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation.
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DOI：
10.1093/nar/gkad030
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发表时间：
2023-02-28
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
--
作者：
改变的eIF4A1活性促进高度结构化的eIF4A1依赖性致癌基因mRNA的翻译，这是致癌翻译程序的根源。目前尚不清楚这些mRNA如何募集和激活eIF4A1解旋特异性地促进其优先翻译。在这里，我们表明，单链RNA序列基序特异性激活eIF4A1解旋，允许在细胞中的eIF4A1依赖的mRNA的局部RNA结构重排和翻译。我们的数据表明，eIF4A1依赖性mRNA在其5'UTR内含有富含AG的基序，其特异性激活eIF4A1解旋局部RNA结构以促进翻译。这种eIF4A1调控模式被编码mTORC信号传导和细胞周期进程组分的mRNA所使用，并使这些mRNA对eIF4A1抑制特别敏感。从机制上讲，我们表明，结合的eIF4A1 AG丰富的序列导致eIF4A1与eIF4A1亚基进行不同的酶活性的多聚化。我们的结构数据表明，多聚体eIF4A1的RNA结合诱导RNA的构象变化，导致eIF4A1最佳定位在RNA双链体附近，从而实现有效的解旋。我们的数据提出了一个模型，其中在eIF4A1依赖性mRNAs的5'UTR中的AG基序特异性激活eIF4A1，使解旋酶活性多聚体eIF4A1复合物的组装成为可能，并将这些复合物定位在稳定的局部RNA结构附近，从而允许核糖体亚基扫描。
Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5’UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5’UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.
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影响因子：
14.9
作者：
Hilbert M;Kebbel F;Gubaev A;Klostermeier D
通讯作者：
Klostermeier D
影响因子：
4.5
作者：
Galicia-Vazquez, Gabriela;Cencic, Regina;Pelletier, Jerry
通讯作者：
Pelletier, Jerry
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
64.8
作者：
Hondele, Maria;Sachdev, Ruchika;Weis, Karsten
通讯作者：
Weis, Karsten
影响因子：
6.1
作者：
Kozin, MB;Svergun, DI
通讯作者：
Svergun, DI