Cleavage of poly(A)-binding protein by poliovirus 3C protease inhibits host cell translation: a novel mechanism for host translation shutoff
Cleavage of poly(A)-binding protein by poliovirus 3C protease inhibits host cell translation: a novel mechanism for host translation shutoff
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DOI：
10.1128/mcb.24.4.1779-1790.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Lloyd, RE
中科院分区：
文献类型：
--
作者：
Kuyumcu-Martinez, NM;Van Eden, ME;Lloyd, RE
病毒2A蛋白酶（2Apro）切割真核生物翻译起始因子4GI（eIF 4GI）已被提出在脊髓灰质炎病毒感染的细胞中引起严重的翻译抑制。然而，含有ImM盐酸胍的感染导致eIF 4GI裂解，但仅部分翻译关闭，表明eIF 4GI裂解不足以进行剧烈的翻译抑制。病毒3C蛋白酶（3Cpro）切割多聚腺苷酸结合蛋白（PABP）并去除与几种翻译因子相互作用的C末端结构域（CTD）。在显示帽-聚（A）协同作用的HeLa细胞翻译提取物中，3Cpro对PABP的部分切割与2Apro对eIF 4GI和eIF 4GII的完全切割一样有效地抑制内源性mRNA和报告RNA的翻译。3Cpro介导的翻译抑制是poly（A）依赖性的，向提取物中添加PABP可以恢复翻译。在HeLa细胞中表达3Cpro导致部分PABP切割和类似的翻译抑制。PABP切割不影响eIF 4GI-PABP相互作用，动力学实验结果表明，3Cpro可能抑制翻译或核糖体回收的后期步骤。这些数据说明了PABP的CTD在哺乳动物细胞中polly（A）依赖性翻译中的重要性。我们建议肠道病毒使用双重策略宿主翻译关闭，需要切割PABP的3Cpro和eIF 4G的2Apro。
Cleavage of eukaryotic translation initiation factor 4GI (eIF4GI) by viral 2A protease (2Apro) has been proposed to cause severe translation inhibition in poliovirus-infected cells. However, infections containing I mM guanidine-HCl result in eIF4GI cleavage but only partial translation shutoff, indicating eIF4GI cleavage is insufficient for drastic translation inhibition. Viral 3C protease (3Cpro) cleaves poly(A)-binding protein (PABP) and removes the C-terminal domain (CTD) that interacts with several translation factors. In HeLa cell translation extracts that exhibit cap-poly(A) synergy, partial cleavage of PABP by 3Cpro inhibited translation of endogenous mRNAs and reporter RNA as effectively as complete cleavage of eIF4GI and eIF4GII by 2Apro. 3Cpro-mediated translation inhibition was poly(A) dependent, and addition of PABP to extracts restored translation. Expression of 3Cpro in HeLa cells resulted in partial PABP cleavage and similar inhibition of translation. PABP cleavage did not affect eIF4GI-PABP interactions, and the results of kinetics experiments suggest that 3Cpro might inhibit late steps in translation or ribosome recycling. The data illustrate the importance of the CTD of PABP in polly(A)-dependent translation in mammalian cells. We propose that enteroviruses use a dual strategy for host translation shutoff, requiring cleavage of PABP by 3Cpro and of eIF4G by 2Apro.