The 5'-poly(A) leader of poxvirus mRNA confers a translational advantage that can be achieved in cells with impaired cap-dependent translation.
The 5'-poly(A) leader of poxvirus mRNA confers a translational advantage that can be achieved in cells with impaired cap-dependent translation.
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DOI：
10.1371/journal.ppat.1006602
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发表时间：
2017-08
期刊：
影响因子：
6.7
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Dhungel P;Cao S;Yang Z
位于5 '-非翻译区（5'-UTR）的poly（A）前导序列是病毒DNA复制后转录的所有痘病毒mRNA（复制后mRNA）的一个异常显著的特征。这些poly（A）前导序列是非模板化的并且具有异质长度;并且它们在痘病毒感染期间的功能仍然是一个长期存在的问题。在这里，我们发现5 '-poly（A）前导序列赋予痘病毒感染细胞中mRNA选择性翻译优势。具有12个残基的组成型和不间断的5 '-poly（A）前导序列是最佳的。由于5 '-poly（A）前导序列的最常见长度为8-12个残基，因此结果表明poly（A）前导序列已被进化优化以促进痘病毒蛋白质的产生。5 '-poly（A）前导序列还可以增加痘病毒原型成员痘苗病毒的基于噬菌体T7启动子的表达系统中的蛋白质产量。有趣的是，尽管牛痘病毒复制后mRNA确实具有5 '-甲基化的鸟苷帽，并且可以使用帽依赖性翻译，但在牛痘病毒感染的细胞中，具有5'-poly（A）前导序列的mRNA也可以在帽依赖性翻译受损的细胞中有效翻译。然而，翻译不是通过内部核糖体进入位点（IRES）介导的。这些结果指出了痘病毒用于有效翻译其复制后mRNA的基本机制。尽管人类历史上最致命的疾病天花已被根除，但痘病毒仍继续对公共卫生产生重大影响。作为一种工具，痘病毒正在被改造用于治疗各种传染病和多种癌症。病毒DNA复制后转录的所有痘病毒mRNA在其5 '-非翻译区都有一个poly（A）前导序列，其功能仍然难以捉摸，代表了我们对控制痘病毒基因表达的基本机制的理解中的一个主要空白。在痘病毒感染的细胞中，发现5 '-poly（A）前导序列赋予痘病毒mRNA翻译优势，这可以在帽依赖性翻译受损的细胞中实现，帽依赖性翻译用于大多数真核mRNA的翻译。此外，由于病毒通常利用现有的细胞功能，因此这些结果很可能指向未知的细胞mRNA翻译机制。因此，这些发现将有助于靶向痘病毒复制后mRNA翻译，以开发新的抗病毒策略。当使用基于噬菌体T7启动子的痘病毒表达系统时，聚（A）前导序列也可用于增加外源基因表达。
The poly(A) leader at the 5’-untranslated region (5’-UTR) is an unusually striking feature of all poxvirus mRNAs transcribed after viral DNA replication (post-replicative mRNAs). These poly(A) leaders are non-templated and of heterogeneous lengths; and their function during poxvirus infection remains a long-standing question. Here, we discovered that a 5’-poly(A) leader conferred a selective translational advantage to mRNA in poxvirus-infected cells. A constitutive and uninterrupted 5’-poly(A) leader with 12 residues was optimal. Because the most frequent lengths of the 5’-poly(A) leaders are 8–12 residues, the result suggests that the poly(A) leader has been evolutionarily optimized to boost poxvirus protein production. A 5’-poly(A) leader also could increase protein production in the bacteriophage T7 promoter-based expression system of vaccinia virus, the prototypic member of poxviruses. Interestingly, although vaccinia virus post-replicative mRNAs do have 5’- methylated guanosine caps and can use cap-dependent translation, in vaccinia virus-infected cells, mRNA with a 5’-poly(A) leader could also be efficiently translated in cells with impaired cap-dependent translation. However, the translation was not mediated through an internal ribosome entry site (IRES). These results point to a fundamental mechanism poxvirus uses to efficiently translate its post-replicative mRNAs. Poxviruses continue to impact public health significantly, despite the eradication of smallpox, the deadliest disease in human history. As a tool, poxviruses are being engineered to treat various infectious diseases and multiple cancers. All poxvirus mRNAs transcribed after viral DNA replication have a poly(A) leader in their 5’-untranslated regions, the function of which remains elusive and represents a major gap in our understanding of the mechanisms fundamental to controlling poxvirus gene expression. In poxvirus-infected cells, a 5’-poly(A) leader was found to confer on poxvirus mRNAs a translational advantage that could be achieved in cells with impaired cap-dependent translation, which is used for translation of most eukaryotic mRNAs. Furthermore, since viruses typically exploit existing cellular functions, it is highly likely that these results point to an unknown cellular mRNA translation mechanism. Thus, the findings should facilitate targeting of poxvirus post-replicative mRNA translation for the development of novel antiviral strategies. The poly(A) leader can also be used to increase foreign gene expression when using the bacteriophage T7 promoter-based poxvirus expression systems.
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