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Interaction of 2A proteinase of human rhinovirus genetic group A with eIF4E is required for eIF4G cleavage during infection
Virology ( IF 2.8 ) Pub Date : 2017-08-29 , DOI: 10.1016/j.virol.2017.08.020
Martina Aumayr , Anna Schrempf , Öykü Üzülmez , Karin M. Olek , Tim Skern

In enteroviruses, the inhibition of protein synthesis from capped host cell mRNA is catalyzed by the virally encoded 2A proteinase (2Apro), which cleaves eukaryotic initiation factors (eIF) 4GI and 4GII. Despite much investigation, the exact mechanism of 2Apro cleavage remains however unclear. Here, we identify the domains responsible for the eIF4E/HRV2 2Apro interaction using molecular modelling and describe mutations that impair this interaction and delay in vitro cleavage of eIF4G isoforms. Furthermore, we produced HRV1A viruses bearing the mutation L17R, Y32A or Y86A in the 2Apro sequence. All three viruses showed reduced yield and were appreciably delayed during infection in eIF4GI cleavage. Thus, we propose for genetic group A HRVs that the eIF4E/2Apro interaction is essential for successful viral replication. In contrast, HRV4 2Apro and coxsackievirus B4 2Apro failed to form complexes with eIF4E, suggesting that the mechanism of eIF4G isoform cleavage in these and related viruses is different.



中文翻译:

人类鼻病毒基因组A的2A蛋白酶与eIF4E相互作用是感染期间eIF4G切割所必需的

在肠病毒中,病毒编码的2A蛋白酶(2A pro)催化了从带帽宿主细胞mRNA合成蛋白质的抑制作用,该酶裂解了真核起始因子(eIF)4GI和4GII。尽管进行了很多研究,但2A前体裂解的确切机制仍不清楚。在这里,我们使用分子模型确定负责eIF4E / HRV2 2A相互作用的域,并描述了削弱该相互作用并延迟eIF4G同工型体外裂解的突变。此外,我们还生产了在2A pro中带有L17R,Y32A或Y86A突变的HRV1A病毒顺序。所有三种病毒均显示出降低的产量,并且在感染eIF4GI的过程中明显延迟。因此,我们建议遗传A组HRVs eIF4E / 2A相互作用对于成功的病毒复制是必不可少的。相反,HRV4 2A pro和柯萨奇病毒B4 2A pro无法与eIF4E形成复合物,这表明在这些病毒和相关病毒中eIF4G同工型裂解的机制是不同的。

更新日期:2017-08-29
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