Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia.
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119234, Russia.
Nucleic Acids Res. 2022 Jan 25;50(2):1111-1127. doi: 10.1093/nar/gkab1286.
eIF4G2 (DAP5 or Nat1) is a homologue of the canonical translation initiation factor eIF4G1 in higher eukaryotes but its function remains poorly understood. Unlike eIF4G1, eIF4G2 does not interact with the cap-binding protein eIF4E and is believed to drive translation under stress when eIF4E activity is impaired. Here, we show that eIF4G2 operates under normal conditions as well and promotes scanning downstream of the eIF4G1-mediated 40S recruitment and cap-proximal scanning. Specifically, eIF4G2 facilitates leaky scanning for a subset of mRNAs. Apparently, eIF4G2 replaces eIF4G1 during scanning of 5' UTR and the necessity for eIF4G2 only arises when eIF4G1 dissociates from the scanning complex. In particular, this event can occur when the leaky scanning complexes interfere with initiating or elongating 80S ribosomes within a translated uORF. This mechanism is therefore crucial for higher eukaryotes which are known to have long 5' UTRs with highly frequent uORFs. We suggest that uORFs are not the only obstacle on the way of scanning complexes towards the main start codon, because certain eIF4G2 mRNA targets lack uORF(s). Thus, higher eukaryotes possess two distinct scanning complexes: the principal one that binds mRNA and initiates scanning, and the accessory one that rescues scanning when the former fails.
eIF4G2（DAP5 或 Nat1）是高等真核生物中经典翻译起始因子 eIF4G1 的同源物，但它的功能仍知之甚少。与 eIF4G1 不同，eIF4G2 不与帽结合蛋白 eIF4E 相互作用，据信在 eIF4E 活性受损时，eIF4G2 在应激下驱动翻译。在这里，我们表明 eIF4G2 在正常条件下也起作用，并促进 eIF4G1 介导的 40S 募集和帽近端扫描下游的扫描。具体来说，eIF4G2 促进了一部分 mRNA 的渗漏扫描。显然，eIF4G2 在 5'UTR 的扫描过程中取代了 eIF4G1，只有当 eIF4G1 从扫描复合物中解离时，eIF4G2 的必要性才会出现。特别是，当渗漏扫描复合物干扰翻译起始或延伸翻译起始密码子上游区 (uORF) 内的 80S 核糖体时，就会发生这种情况。因此，这种机制对于具有长 5'UTR 和高度频繁 uORF 的高等真核生物至关重要。我们认为，uORF 并不是扫描复合物向主要起始密码子前进的唯一障碍，因为某些 eIF4G2 mRNA 靶标缺乏 uORF(s)。因此，高等真核生物拥有两种不同的扫描复合物：一种是结合 mRNA 并起始扫描的主要复合物，另一种是当前者失败时挽救扫描的辅助复合物。
