PDF(Pubmed)
Abstract：
Upstream open reading frames (uORFs) are a frequent feature of eukaryotic mRNAs. Upstream ORFs govern main ORF translation in a variety of ways, but, in a nutshell, they either filter out scanning ribosomes or allow downstream translation initiation via leaky scanning or reinitiation. Previous reports concurred that eIF4G2, a long-known but insufficiently studied eIF4G1 homologue, can rescue the downstream translation, but disagreed on whether it is leaky scanning or reinitiation that eIF4G2 promotes. Here, we investigated a unique human mRNA that encodes two highly conserved proteins (POLGARF with unknown function and POLG, the catalytic subunit of the mitochondrial DNA polymerase) in overlapping reading frames downstream of a regulatory uORF. We show that the uORF renders the translation of both POLGARF and POLG mRNAs reliant on eIF4G2. Mechanistically, eIF4G2 enhances both leaky scanning and reinitiation, and it appears that ribosomes can acquire eIF4G2 during the early steps of reinitiation. This emphasizes the role of eIF4G2 as a multifunctional scanning guardian that replaces eIF4G1 to facilitate ribosome movement but not ribosome attachment to an mRNA.
摘要：
上游开放阅读框(uORF)是真核mRNAs的常见特征。上游ORF以各种方式管理主要的ORF翻译，但是,简而言之，它们要么过滤掉扫描核糖体，要么通过泄漏扫描或重新开始允许下游翻译开始。先前的报道同意eIF4G2，一种长期已知但研究不足的eIF4G1同源物，可以拯救下游的翻译，但不同意eIF4G2促进的是泄漏扫描还是重新启动。这里,我们研究了一种独特的人类mRNA，该mRNA编码两种高度保守的蛋白质（具有未知功能的POLGARF和POLG，线粒体DNA聚合酶的催化亚基）在调节性uORF下游的重叠阅读框中。我们表明，uORF使POLGARF和POLGmRNA的翻译都依赖于eIF4G2。机械上,eIF4G2增强了泄漏扫描和重新启动，似乎核糖体可以在重新启动的早期步骤中获得eIF4G2。这强调了eIF4G2作为多功能扫描监护人的作用，它取代eIF4G1以促进核糖体运动，但不促进核糖体与mRNA的连接。
