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甲病毒信使核糖核酸中的一种核糖核酸捕获机制促进核糖体停滞和翻译起始。

An RNA trapping mechanism in Alphavirus mRNA promotes ribosome stalling and translation initiation.

作者信息

Toribio René, Díaz-López Irene, Boskovic Jasminka, Ventoso Iván

机构信息

Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM) and Departamento de Biología Molecular, Universidad Autónoma de Madrid (UAM), Madrid, Spain.

Structural Biology and Biocomputing Programme, Electron Microscopy Unit, Spanish Nacional Cancer Research Center (CNIO), 28029 Madrid, Spain.

出版信息

Nucleic Acids Res. 2016 May 19;44(9):4368-80. doi: 10.1093/nar/gkw172. Epub 2016 Mar 16.

DOI:10.1093/nar/gkw172
PMID:26984530
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4872096/
Abstract

During translation initiation, eukaryotic initiation factor 2 (eIF2) delivers the Met-tRNA to the 40S ribosomal subunit to locate the initiation codon (AUGi) of mRNA during the scanning process. Stress-induced eIF2 phosphorylation leads to a general blockade of translation initiation and represents a key antiviral pathway in mammals. However, some viral mRNAs can initiate translation in the presence of phosphorylated eIF2 via stable RNA stem-loop structures (DLP; Downstream LooP) located in their coding sequence (CDS), which promote 43S preinitiation complex stalling on the initiation codon. We show here that during the scanning process, DLPs of Alphavirus mRNA become trapped in ES6S region (680-914 nt) of 18S rRNA that are projected from the solvent side of 40S subunit. This trapping can lock the progress of the 40S subunit on the mRNA in a way that places the upstream initiator AUGi on the P site of 40S subunit, obviating the participation of eIF2. Notably, the DLP structure is released from 18S rRNA upon 60S ribosomal subunit joining, suggesting conformational changes in ES6Ss during the initiation process. These novel findings illustrate how viral mRNA is threaded into the 40S subunit during the scanning process, exploiting the topology of the 40S subunit solvent side to enhance its translation in vertebrate hosts.

摘要

在翻译起始过程中，真核起始因子2（eIF2）将甲硫氨酰 - tRNA递送至40S核糖体亚基，以便在扫描过程中定位mRNA的起始密码子（AUGi）。应激诱导的eIF2磷酸化导致翻译起始的普遍阻滞，并代表哺乳动物中的关键抗病毒途径。然而，一些病毒mRNA可以通过位于其编码序列（CDS）中的稳定RNA茎环结构（DLP；下游环）在磷酸化的eIF2存在下起始翻译，该结构促进43S预起始复合物在起始密码子处停滞。我们在此表明，在扫描过程中，甲病毒mRNA的DLP被困在从40S亚基的溶剂侧突出的18S rRNA的ES6S区域（680 - 914 nt）中。这种捕获可以锁定40S亚基在mRNA上的进程，使上游起始AUGi位于40S亚基的P位点，从而无需eIF2的参与。值得注意的是，当60S核糖体亚基加入时，DLP结构从18S rRNA释放，表明在起始过程中ES6S发生构象变化。这些新发现说明了病毒mRNA在扫描过程中如何穿入40S亚基，利用40S亚基溶剂侧的拓扑结构来增强其在脊椎动物宿主中的翻译。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/8662ecce9d7e/gkw172fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/30a375a38b1a/gkw172fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/ed0fc21998b1/gkw172fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/0e5506359efa/gkw172fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/4c6fb1192bcb/gkw172fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/a0d8e5e7734c/gkw172fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/6d92199d845b/gkw172fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/ad8ff3c619ae/gkw172fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/d587983bb1b7/gkw172fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/8662ecce9d7e/gkw172fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/30a375a38b1a/gkw172fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/ed0fc21998b1/gkw172fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/0e5506359efa/gkw172fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/4c6fb1192bcb/gkw172fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/a0d8e5e7734c/gkw172fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/6d92199d845b/gkw172fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/ad8ff3c619ae/gkw172fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/d587983bb1b7/gkw172fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a936/4872096/8662ecce9d7e/gkw172fig9.jpg

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