Department of Microbiology, NYU School of Medicine, New York, NY, USA.
Department of Microbiology, NYU School of Medicine, New York, NY, USA; Institute of Virology, Hannover Medical School, Hannover, Germany.
Cell Rep. 2022 May 3;39(5):110767. doi: 10.1016/j.celrep.2022.110767.
Regulated loading of eIF3-bound 40S ribosomes on capped mRNA is generally dependent upon the translation initiation factor eIF4E; however, mRNA translation often proceeds during physiological stress, such as virus infection, when eIF4E availability and activity are limiting. It remains poorly understood how translation of virus and host mRNAs are regulated during infection stress. While initially sensitive to mTOR inhibition, which limits eIF4E-dependent translation, we show that protein synthesis in human cytomegalovirus (HCMV)-infected cells unexpectedly becomes progressively reliant upon eIF3d. Targeting eIF3d selectively inhibits HCMV replication, reduces polyribosome abundance, and interferes with expression of essential virus genes and a host gene expression signature indicative of chronic ER stress that fosters HCMV reproduction. This reveals a strategy whereby cellular eIF3d-dependent protein production is hijacked to exploit virus-induced ER stress. Moreover, it establishes how switching between eIF4E and eIF3d-responsive cap-dependent translation can differentially tune virus and host gene expression in infected cells.
调节 eIF3 结合的 40S 核糖体在帽状 mRNA 上的加载通常依赖于翻译起始因子 eIF4E；然而，在生理应激（如病毒感染）期间，eIF4E 的可用性和活性受到限制，mRNA 翻译往往会进行。在感染应激期间，病毒和宿主 mRNA 的翻译是如何被调节的，这仍然知之甚少。尽管最初对限制 eIF4E 依赖性翻译的 mTOR 抑制剂敏感，但我们发现人巨细胞病毒（HCMV）感染细胞中的蛋白质合成出人意料地越来越依赖于 eIF3d。靶向 eIF3d 选择性抑制 HCMV 复制，减少多核糖体丰度，并干扰必需病毒基因和宿主基因表达特征的表达，这些特征表明内质网应激呈慢性，促进 HCMV 繁殖。这揭示了一种策略，即细胞内的 eIF3d 依赖性蛋白质产生被劫持，以利用病毒诱导的内质网应激。此外，它还确定了 eIF4E 和 eIF3d 响应帽依赖性翻译之间的转换如何在感染细胞中差异调节病毒和宿主基因的表达。
