DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4
DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4
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DOI：
10.1038/s41467-020-18452-2
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发表时间：
2020-09-16
影响因子：
16.6
通讯作者：
Teleman, Aurelio A.
中科院分区：
文献类型：
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作者：
Bohlen, Jonathan;Harbrecht, Liza;Teleman, Aurelio A.
翻译效率在不同的mRNA之间变化很大，从而影响蛋白质表达。应激反应主调节因子ATF 4的翻译在应激时增加，但其分子机制尚不清楚。我们在这里发现，翻译因子DENR，MCTS 1和eIF 2D是诱导ATF 4翻译所需的压力，通过促进翻译重新启动在ATF 4的5 UTR。我们发现，DENR和MCTS 1只需要上游开放阅读框架（uORF）后，含有某些倒数第二个密码子的重新启动，可能是因为DENR中心点MCTS 1只需要驱逐某些tRNA从终止后40 S核糖体。这为DENR和MCTS 1如何促进翻译再起始提供了模型。暴露于许多压力的癌细胞需要ATF 4来存活和增殖。我们发现在癌症中DENR中心点MCTS 1表达和ATF 4活性之间存在很强的相关性。此外，包括a-Raf、c-Raf和Cdk 4的其他癌基因具有长uORF，并且以DENR中心点MCTS 1依赖性方式翻译。在应激时，ATF 4的翻译通过在短上游开放阅读框（uORF）翻译后重新启动核糖体来诱导。在这里，作者表明，ATF 4的翻译重新启动是由DENR-MCTS 1复合物介导的，该复合物作用于含有某些倒数第二个密码子的uORF。
Translation efficiency varies considerably between different mRNAs, thereby impacting protein expression. Translation of the stress response master-regulator ATF4 increases upon stress, but the molecular mechanisms are not well understood. We discover here that translation factors DENR, MCTS1 and eIF2D are required to induce ATF4 translation upon stress by promoting translation reinitiation in the ATF4 5UTR. We find DENR and MCTS1 are only needed for reinitiation after upstream Open Reading Frames (uORFs) containing certain penultimate codons, perhaps because DENR center dot MCTS1 are needed to evict only certain tRNAs from post-termination 40S ribosomes. This provides a model for how DENR and MCTS1 promote translation reinitiation. Cancer cells, which are exposed to many stresses, require ATF4 for survival and proliferation. We find a strong correlation between DENR center dot MCTS1 expression and ATF4 activity across cancers. Furthermore, additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR center dot MCTS1 dependent manner. Upon stress, translation of ATF4 is induced by reinitiating ribosomes following translation of short upstream open reading frames (uORFs). Here the authors show that translation re-initiation of ATF4 is mediated by the DENR-MCTS1 complex which acts on uORFs containing certain penultimate codons.