An eIF3d-dependent switch regulates HCMV replication by remodeling the infected cell translation landscape to mimic chronic ER stress.
An eIF3d-dependent switch regulates HCMV replication by remodeling the infected cell translation landscape to mimic chronic ER stress.
复制标题
依赖eIF3d的开关通过重塑感染细胞的翻译环境来调节HCMV的复制，以模拟慢性内质网应激。
DOI：
10.1016/j.celrep.2022.110767
复制
发表时间：
2022-05-03
期刊：
影响因子：
8.8
通讯作者：
Mohr, Ian
中科院分区：
文献类型：
--
作者：
Thompson, Letitia;Depledge, Daniel P.;Burgess, Hannah M.;Mohr, Ian
eif3结合的40S核糖体在被盖住的mRNA上的装载通常依赖于翻译起始因子eIF4E；然而，当eIF4E的可用性和活性受到限制时，mRNA翻译通常在生理应激期间进行，例如病毒感染。在感染胁迫下，病毒和宿主mrna的翻译是如何被调节的，目前还不清楚。虽然最初对mTOR抑制敏感，这限制了eif4e依赖的翻译，但我们发现人类巨细胞病毒（HCMV）感染细胞中的蛋白质合成意外地逐渐依赖于eIF3d。靶向eIF3d选择性抑制HCMV复制，降低多核糖体丰度，干扰必需病毒基因的表达和宿主基因表达标志，表明慢性内质网应激促进HCMV繁殖。这揭示了一种策略，即利用病毒诱导的内质网应激劫持细胞依赖eif3d的蛋白质生产。此外，它还确定了eIF4E和eif3d响应性帽依赖翻译之间的切换如何在感染细胞中对病毒和宿主基因表达进行差异调节。Thompson等人的研究表明，hcmv感染细胞中受限制的mRNA翻译依赖于eIF3d，而不是eif4e调节的核糖体装载。消耗eIF3d抑制HCMV复制，减少多核糖体，限制病毒晚期基因和宿主慢性内质网应激诱导的基因表达。因此，切换到eif3d响应翻译调整基因表达以支持病毒复制。
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. Instead of eIF4E-regulated ribosome loading, Thompson et al. show capped mRNA translation in HCMV-infected cells becomes reliant upon eIF3d. Depleting eIF3d inhibits HCMV replication, reduces polyribosomes, and restricts virus late gene and host chronic ER stress-induced gene expression. Thus, switching to eIF3d-responsive translation tunes gene expression to support virus replication.
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DOI：
10.1098/rstb.2016.0176
发表时间：
2017-03-19
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Cate JH
通讯作者：
Cate JH
影响因子：
16
作者：
Guan BJ;van Hoef V;Jobava R;Elroy-Stein O;Valasek LS;Cargnello M;Gao XH;Krokowski D;Merrick WC;Kimball SR;Komar AA;Koromilas AE;Wynshaw-Boris A;Topisirovic I;Larsson O;Hatzoglou M
通讯作者：
Hatzoglou M
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
7.7
作者：
Bianco, Christopher;Mohr, Ian
通讯作者：
Mohr, Ian
影响因子：
16.6
作者：
de la Parra C;Ernlund A;Alard A;Ruggles K;Ueberheide B;Schneider RJ
通讯作者：
Schneider RJ