Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia.
Int J Mol Sci. 2023 Dec 5;24(24):17149. doi: 10.3390/ijms242417149.
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.
上游开放阅读框（uORFs）是真核 mRNA 的常见特征。上游 ORF 通过多种方式控制主 ORF 的翻译，但简而言之，它们要么过滤掉扫描核糖体，要么通过渗漏扫描或重新起始允许下游翻译起始。以前的报告一致认为，eIF4G2 是一种已知但研究不足的 eIF4G1 同源物，可挽救下游翻译，但对 eIF4G2 促进的是渗漏扫描还是重新起始存在分歧。在这里，我们研究了一种独特的人类 mRNA，该 mRNA 在调节 uORF 下游的重叠阅读框中编码两个高度保守的蛋白质（具有未知功能的 POLGARF 和 POLG，线粒体 DNA 聚合酶的催化亚基）。我们表明，uORF 使 POLGARF 和 POLG mRNA 的翻译都依赖于 eIF4G2。从机制上讲，eIF4G2 增强了渗漏扫描和重新起始，而且核糖体似乎可以在重新起始的早期步骤中获得 eIF4G2。这强调了 eIF4G2 作为多功能扫描保护因子的作用，它可以取代 eIF4G1 来促进核糖体运动，但不能促进核糖体与 mRNA 的结合。
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