Conventional and unconventional mechanisms for capping viral mRNA.-猫眼课题宝

DOI：

10.1038/nrmicro2675

发表时间：

2011-12-05

期刊：

Nature reviews. Microbiology

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Decroly E;Ferron F;Lescar J;Canard B

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097100/

mRNA在其5′端受到帽结构的保护，帽结构由通过5′-5′三磷酸键连接到第一个转录核苷酸的N7-甲基化GTP分子组成。帽结构对于RNA剪接、输出和稳定性是必不可少的，并且允许核糖体复合物识别mRNA并确保其有效翻译。未加帽的RNA分子在称为加工体的细胞质颗粒区室中降解，并且可以被宿主细胞检测为“非自身”，通过产生干扰素触发抗病毒先天免疫应答。传统的RNA加帽（即来自宿主细胞和DNA病毒的mRNA）需要通过RNA三磷酸酶水解RNA的5′-γ-磷酸，通过鸟苷酰转移酶将GMP分子转移到RNA的5′-末端，并通过（鸟嘌呤-N7）-甲基转移酶将该鸟苷甲基化。第一个和第二个转录的核苷酸随后被（核苷-2 ′-O）-甲基转移酶甲基化形成cap-1和cap-2结构。病毒已经进化出高度多样的加帽机制，以使用它们自己的或细胞的加帽机制或通过从细胞mRNA窃取帽结构来获得帽结构。病毒编码的RNA加帽机制在其遗传组分、蛋白质结构域组织、酶结构以及反应机制和途径方面是多样的，使得病毒RNA加帽成为抗病毒药物设计的有吸引力的靶标。用7-甲基鸟苷部分封端真核生物mRNA的5′端使得mRNA能够有效地剪接、核输出和翻译，并且还限制了它们被细胞外切核酸酶降解。在这里，Canard及其同事描述了病毒如何合成自己的mRNA帽结构或从宿主mRNA中窃取它们，从而有效合成病毒蛋白并避免宿主先天免疫反应。在真核细胞中，mRNA 5′端的加帽是一种重要的结构修饰，它允许有效的mRNA翻译，指导前体mRNA剪接和mRNA从细胞核输出，限制细胞5′-3′核酸外切酶对mRNA的降解，并允许将外源RNA（包括病毒转录物）识别为“非自身”。然而，病毒已经进化出了保护其RNA 5′端的机制，即用共价连接的肽或帽部分（7-甲基-Gppp，其中p是磷酸基团）保护其RNA 5′端，这与细胞mRNA帽结构无法区分。病毒RNA帽可以从细胞mRNA中窃取或使用宿主或病毒编码的加帽装置合成，并且这些加帽组件在组织，结构和机制方面表现出广泛的多样性。本文综述了真核细胞病毒产生功能性mRNA 5′帽和逃避天然免疫的策略。

mRNAs are protected at their 5′ ends by a cap structure consisting of an N7-methylated GTP molecule linked to the first transcribed nucleotide by a 5′–5′ triphosphate bond. The cap structure is essential for RNA splicing, export and stability, and allows the ribosomal complex to recognize mRNAs and ensure their efficient translation. Uncapped RNA molecules are degraded in cytoplasmic granular compartments called processing bodies and may be detected as 'non-self' by the host cell, triggering antiviral innate immune responses through the production of interferons. Conventional RNA capping (that is, of mRNAs from the host cell and from DNA viruses) requires hydrolysis of the 5′ γ-phosphate of RNA by an RNA triphosphatase, transfer of a GMP molecule onto the 5′-end of RNA by a guanylyltransferase, and methylation of this guanosine by an (guanine-N7)-methyltransferase. Subsequent methylations on the first and second transcribed nucleotides by (nucleoside-2′-O)-methyltransferases form cap-1 and cap-2 structures. Viruses have evolved highly diverse capping mechanisms to acquire cap structures using their own or cellular capping machineries, or by stealing cap structures from cellular mRNAs. Virally encoded RNA-capping machineries are diverse in terms of their genetic components, protein domain organization, enzyme structures, and reaction mechanisms and pathways, making viral RNA capping an attractive target for antiviral-drug design. Capping the 5′ end of eukaryotic mRNAs with a 7-methylguanosine moiety enables efficient splicing, nuclear export and translation of mRNAs, and also limits their degradation by cellular exonucleases. Here, Canard and colleagues describe how viruses synthesize their own mRNA cap structures or steal them from host mRNAs, allowing efficient synthesis of viral proteins and avoidance of host innate immune responses. In the eukaryotic cell, capping of mRNA 5′ ends is an essential structural modification that allows efficient mRNA translation, directs pre-mRNA splicing and mRNA export from the nucleus, limits mRNA degradation by cellular 5′–3′ exonucleases and allows recognition of foreign RNAs (including viral transcripts) as 'non-self'. However, viruses have evolved mechanisms to protect their RNA 5′ ends with either a covalently attached peptide or a cap moiety (7-methyl-Gppp, in which p is a phosphate group) that is indistinguishable from cellular mRNA cap structures. Viral RNA caps can be stolen from cellular mRNAs or synthesized using either a host- or virus-encoded capping apparatus, and these capping assemblies exhibit a wide diversity in organization, structure and mechanism. Here, we review the strategies used by viruses of eukaryotic cells to produce functional mRNA 5′-caps and escape innate immunity.