Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0314 United States.
Biochemistry. 2022 Jul 19;61(14):1485-1494. doi: 10.1021/acs.biochem.2c00019. Epub 2022 Jul 7.
The influenza A virus (IAV) is responsible for seasonal epidemics that result in hundreds of thousands of deaths worldwide annually. The non-structural protein 1 (NS1) of the IAV inflicts various antagonistic processes on the host during infection. These processes include inhibition of the host interferon system, inhibition of the apoptotic response, and enhancement of viral mRNA translation, all of which contribute to the overall virulence of the IAV. Although the mechanism by which NS1 stimulates translation is unknown, NS1 has been shown to bind both poly-A binding Protein 1 and eukaryotic initiation factor 4 gamma 1 (eIF4G1), two proteins necessary for cap-dependent translation. We directly analyzed the interaction between NS1 and eIF4G1 within the context of the 5'-mG-mRNA·eIF4E·eIF4G1 complex. Interestingly, our studies show that NS1 can bind this complex in the presence or absence of 5'-mG-mRNA. Additionally, we were interested in investigating whether NS1 interacts with eIF4E directly. Our results indicate that NS1 can bind to eIF4E only in the absence of 5'-mG-mRNA. Considering previous data, we propose that NS1 stimulates translation by binding to eIF4G1 and recruiting the 43S pre-translation initiation complex to the mRNA.
甲型流感病毒（IAV）是造成全球每年数十万人死亡的季节性流行的罪魁祸首。IAV 的非结构蛋白 1（NS1）在感染过程中对宿主施加了各种拮抗过程。这些过程包括抑制宿主干扰素系统、抑制细胞凋亡反应以及增强病毒 mRNA 翻译，所有这些都有助于 IAV 的整体毒力。虽然 NS1 刺激翻译的机制尚不清楚，但已经表明 NS1 结合多聚 A 结合蛋白 1 和真核起始因子 4 伽马 1（eIF4G1），这两种蛋白是帽依赖翻译所必需的。我们直接在 5'-mG-mRNA·eIF4E·eIF4G1 复合物的背景下分析 NS1 与 eIF4G1 之间的相互作用。有趣的是，我们的研究表明，NS1 可以在存在或不存在 5'-mG-mRNA 的情况下结合此复合物。此外，我们有兴趣研究 NS1 是否直接与 eIF4E 相互作用。我们的结果表明，NS1 只能在不存在 5'-mG-mRNA 的情况下与 eIF4E 结合。考虑到先前的数据，我们提出 NS1 通过与 eIF4G1 结合并将 43S 预翻译起始复合物募集到 mRNA 上来刺激翻译。
