Poxvirus-encoded decapping enzymes promote selective translation of viral mRNAs.
Poxvirus-encoded decapping enzymes promote selective translation of viral mRNAs.
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DOI：
10.1371/journal.ppat.1008926
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发表时间：
2020-10
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：
Cantu F;Cao S;Hernandez C;Dhungel P;Spradlin J;Yang Z
细胞脱帽酶通过去除真核 mRNA 5' 端的甲基鸟苷帽来负向调节基因表达，使 mRNA 易于降解并抑制 mRNA 翻译。痘苗病毒 (VACV) 是痘病毒的原型，编码两种脱帽酶 D9 和 D10，可诱导细胞和病毒 mRNA 的降解。通过全基因组翻译效率调查，我们分析了感染野生型 VACV 和具有灭活脱帽酶的突变 VACV 的细胞中的痘苗病毒 mRNA。我们发现，VACV 脱帽酶是病毒复制后 mRNA（病毒 DNA 复制后转录）的选择性翻译所必需的，与 PKR 和 RNase L 介导的翻译抑制无关。进一步的分子表征表明，VACV 脱帽酶对于具有 5'-poly(A) 前导序列的 mRNA 的有效翻译是必需的，该前导序列存在于所有病毒复制后 mRNA 中。 VACV 中单独的 D10 失活会显着损害多聚腺苷酸前导序列介导的翻译。值得注意的是，在没有 VACV 感染的情况下，D10 会刺激 mRNA 翻译，并优先选择含有 5'-poly(A) 前导序列的 RNA。我们进一步发现，VACV 脱帽酶是感染过程中 5’-poly(A) 前导序列介导的帽独立翻译增强所必需的。我们的研究结果确定了一种机制，通过破坏病毒脱帽酶来刺激 5'-poly(A) 前导序列介导的翻译，选择性翻译 VACV mRNA。脱帽酶在真核细胞和一些病毒中编码。先前的研究表明，脱帽酶通过加速 mRNA 降解和抑制翻译而成为负基因表达调节剂。然而，令人惊讶的是，在这项研究中，我们发现痘苗病毒 (VACV) 编码的脱帽酶 D9 和 D10 是促进病毒蛋白选择性合成所必需的，尽管已知它们会促进细胞和病毒 mRNA 降解。我们进一步表明，VACV mRNA 的不寻常的 5'-UTR（5'-poly(A) 前导序列）为痘苗病毒感染期间脱帽酶促进的 mRNA 翻译赋予了优势。此外，D9 和 D10 对于在 VACV 感染期间刺激多聚腺苷酸前导序列介导的帽独立翻译增强是必需的。在没有 VACV 感染的情况下，单独的 D10 以脱帽活性依赖性方式刺激 mRNA 翻译，并优先选择含有 Poly(A) 前导序列的 mRNA。 D10 对 mRNA 翻译的刺激在脱帽酶中是独一无二的。因此，我们发现了一种通过病毒 mRNA 5'-UTR 和病毒编码的脱帽酶协调选择性合成 VACV 蛋白的新机制。
Cellular decapping enzymes negatively regulate gene expression by removing the methylguanosine cap at the 5’ end of eukaryotic mRNA, rendering mRNA susceptible to degradation and repressing mRNA translation. Vaccinia virus (VACV), the prototype poxvirus, encodes two decapping enzymes, D9 and D10, that induce the degradation of both cellular and viral mRNAs. Using a genome-wide survey of translation efficiency, we analyzed vaccinia virus mRNAs in cells infected with wild type VACV and mutant VACVs with inactivated decapping enzymes. We found that VACV decapping enzymes are required for selective translation of viral post-replicative mRNAs (transcribed after viral DNA replication) independent of PKR- and RNase L-mediated translation repression. Further molecular characterization demonstrated that VACV decapping enzymes are necessary for efficient translation of mRNA with a 5'-poly(A) leader, which are present in all viral post-replicative mRNAs. Inactivation of D10 alone in VACV significantly impairs poly(A)-leader-mediated translation. Remarkably, D10 stimulates mRNA translation in the absence of VACV infection with a preference for RNA containing a 5’-poly(A) leader. We further revealed that VACV decapping enzymes are needed for 5’-poly(A) leader-mediated cap-independent translation enhancement during infection. Our findings identified a mechanism by which VACV mRNAs are selectively translated through subverting viral decapping enzymes to stimulate 5’-poly(A) leader-mediated translation. Decapping enzymes are encoded in eukaryotic cells and some viruses. Previous studies indicated that decapping enzymes are negative gene expression regulators by accelerating mRNA degradation and repressing translation. Surprisingly however, in this study we found that vaccinia virus (VACV) encoded-decapping enzymes, D9 and D10, are required to promote selective synthesis of viral proteins, although they are known to promote both cellular and viral mRNA degradation. We further showed that the unusual 5'-UTR of VACV mRNA, the 5'-poly(A) leader, confers an advantage to mRNA translation promoted by the decapping enzymes during vaccinia virus infection. Moreover, D9 and D10 are necessary for stimulating poly(A)-leader-mediated cap-independent translation enhancement during VACV infection. In the absence of VACV infection, D10 alone stimulates mRNA translation in a decapping activity-dependent manner, with a preference for mRNA that contains a poly(A) leader. The stimulation of mRNA translation by D10 is unique among decapping enzymes. Therefore, we identified a new mechanism to selectively synthesize VACV proteins through a coordination of viral mRNA 5’-UTR and virus-encoded decapping enzymes.
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影响因子：
14.9
作者：
Drummond SP;Hildyard J;Firczuk H;Reamtong O;Li N;Kannambath S;Claydon AJ;Beynon RJ;Eyers CE;McCarthy JE
通讯作者：
McCarthy JE
DOI：
10.1007/978-1-4939-9593-6_10
发表时间：
2019-01-01
期刊：
VACCINIA VIRUS
影响因子：
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作者：
Cao, Shuai;Lin, Yongquan;Yang, Zhilong
通讯作者：
Yang, Zhilong
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
1.2
作者：
Dhungel, Pragyesh;Cantu, Fernando;Yang, Zhilong
通讯作者：
Yang, Zhilong
影响因子：
56.9
作者：
Gilbert, Wendy V.;Zhou, Kaihong;Doudna, Jennifer A.
通讯作者：
Doudna, Jennifer A.