Interaction of 2A proteinase of human rhinovirus genetic group A with eIF4E is required for eIF4G cleavage during infection
Interaction of 2A proteinase of human rhinovirus genetic group A with eIF4E is required for eIF4G cleavage during infection
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DOI：
10.1016/j.virol.2017.08.020
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发表时间：
2017-11-01
期刊：
影响因子：
3.7
通讯作者：
Skern, Tim
中科院分区：
文献类型：
--
作者：
Aumayr, Martina;Schrempf, Anna;Skern, Tim
在肠道病毒中，病毒编码的 2A 蛋白酶 (2A(Pro)) 会抑制带帽宿主细胞 mRNA 的蛋白质合成，该蛋白酶会裂解真核起始因子 (eIF) 4GI 和 4GII。尽管进行了大量研究，2AP(ro) 裂解的确切机制仍不清楚。在这里，我们使用分子模型确定了负责 eIF4E/HRV2 2AP(ro) 相互作用的结构域，并描述了损害这种相互作用并延迟 eIF4G 同种型体外裂解的突变。此外，我们生产了在2AP(ro)序列中带有突变L17R、Y32A或Y86A的HRV1A病毒。所有三种病毒均表现出产量降低，并且在感染过程中 eIF4GI 裂解明显延迟。因此，我们建议对于遗传 A 组 HRV，eIF4E/2A(Pro) 相互作用对于成功的病毒复制至关重要。相比之下，HRV4 2A(Pro)和柯萨奇病毒B4 2A(Pro)未能与eIF4E形成复合物，这表明这些病毒和相关病毒中eIF4G亚型裂解的机制是不同的。
In enteroviruses, the inhibition of protein synthesis from capped host cell mRNA is catalyzed by the virally encoded 2A proteinase (2A(Pro)), which cleaves eukaryotic initiation factors (eIF) 4GI and 4GII. Despite much investigation, the exact mechanism of 2AP(ro) cleavage remains however unclear. Here, we identify the domains responsible for the eIF4E/HRV2 2AP(ro) 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 2AP(ro) 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/2A(Pro) interaction is essential for successful viral replication. In contrast, HRV4 2A(Pro) and coxsackievirus B4 2A(Pro) failed to form complexes with eIF4E, suggesting that the mechanism of eIF4G isoform cleavage in these and related viruses is different.