Middle East Respiratory Syndrome Coronavirus nsp1 Inhibits Host Gene Expression by Selectively Targeting mRNAs Transcribed in the Nucleus while Sparing mRNAs of Cytoplasmic Origin
Middle East Respiratory Syndrome Coronavirus nsp1 Inhibits Host Gene Expression by Selectively Targeting mRNAs Transcribed in the Nucleus while Sparing mRNAs of Cytoplasmic Origin
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DOI：
10.1128/jvi.01352-15
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发表时间：
2015-11-01
影响因子：
5.4
通讯作者：
Makino, Shinji
中科院分区：
文献类型：
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作者：
Lokugamage, Kumari G.;Narayanan, Krishna;Makino, Shinji
新出现的中东呼吸综合征冠状病毒(MERS-CoV)和严重急性呼吸综合征冠状病毒(SARS-CoV)是高致病性人类冠状病毒，具有在转录后水平抑制宿主基因表达的特性。与SARS-CoV的非结构蛋白1(NSP1)在翻译水平上抑制宿主基因表达类似，我们报道MERS-CoV NSP1也具有保守的功能，通过抑制宿主mRNA的翻译和诱导宿主mRNAs的降解来负调控宿主基因的表达。此外，与SARS-CoV NSP1一样，MERS-CoV NSP1的mRNA降解活性与其翻译抑制功能是可分离的，这种降解活性最可能是由其诱导内核裂解RNA的能力引发的。尽管有这些功能上的相似之处，MERS-CoV nsp1使用了一种截然不同的策略，选择性地针对具有翻译能力的宿主mRNAs进行抑制。SARS-CoV NSP1仅定位于细胞质，并与40S核糖体亚基结合以获得翻译的mRNAs，而MERS-CoV NSP1分布在细胞核和细胞质中，并不稳定地与40s亚基结合，提示靶向翻译mRNAs的方式明显不同。有趣的是，与这一概念一致，MERS-CoV nsp1选择性地针对在细胞核中转录并运输到细胞质的mRNAs，以抑制翻译和mRNA的降解，但避免了直接引入细胞质的外源mRNAs或起源于细胞质的类似病毒的mRNAs。总之，这些数据指向一种新的病毒策略，其中MERS-CoV mRNAs的细胞质来源有助于它们逃避MERS-CoV nsp1的抑制作用。中东呼吸综合征冠状病毒(MERS-CoV)是2012年在沙特阿拉伯出现的一种高致病性人类冠状病毒。MERS冠状病毒起源于人畜共患病，对公众健康构成重大威胁。然而，对导致MERS冠状病毒高毒力的病毒因素知之甚少。包括冠状病毒在内的许多动物病毒编码的蛋白质会干扰宿主基因的表达，包括那些参与抗病毒免疫反应的蛋白质，而这些病毒蛋白质往往是主要的毒力因素。冠状病毒的非结构蛋白1(NSP1)是一种抑制宿主基因表达的蛋白，是主要的毒力因子。这项研究为MERS冠状病毒nsp1使用的策略提供了证据，以抑制宿主基因的表达，这是以前对任何病毒蛋白都没有描述的。本研究是更好地理解MERS冠状病毒毒力和致病机制的因素和分子机制的有意义的一步。
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome CoV (SARS-CoV) represent highly pathogenic human CoVs that share a property to inhibit host gene expression at the posttranscriptional level. Similar to the nonstructural protein 1 (nsp1) of SARS-CoV that inhibits host gene expression at the translational level, we report that MERS-CoV nsp1 also exhibits a conserved function to negatively regulate host gene expression by inhibiting host mRNA translation and inducing the degradation of host mRNAs. Furthermore, like SARS-CoV nsp1, the mRNA degradation activity of MERS-CoV nsp1, most probably triggered by its ability to induce an endonucleolytic RNA cleavage, was separable from its translation inhibitory function. Despite these functional similarities, MERS-CoV nsp1 used a strikingly different strategy that selectively targeted translationally competent host mRNAs for inhibition. While SARS-CoV nsp1 is localized exclusively in the cytoplasm and binds to the 40S ribosomal subunit to gain access to translating mRNAs, MERS-CoV nsp1 was distributed in both the nucleus and the cytoplasm and did not bind stably to the 40S subunit, suggesting a distinctly different mode of targeting translating mRNAs. Interestingly, consistent with this notion, MERS-CoV nsp1 selectively targeted mRNAs, which are transcribed in the nucleus and transported to the cytoplasm, for translation inhibition and mRNA degradation but spared exogenous mRNAs introduced directly into the cytoplasm or virus-like mRNAs that originate in the cytoplasm. Collectively, these data point toward a novel viral strategy wherein the cytoplasmic origin of MERS-CoV mRNAs facilitates their escape from the inhibitory effects of MERS-CoV nsp1.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human CoV that emerged in Saudi Arabia in 2012. MERS-CoV has a zoonotic origin and poses a major threat to public health. However, little is known about the viral factors contributing to the high virulence of MERS-CoV. Many animal viruses, including CoVs, encode proteins that interfere with host gene expression, including those involved in antiviral immune responses, and these viral proteins are often major virulence factors. The nonstructural protein 1 (nsp1) of CoVs is one such protein that inhibits host gene expression and is a major virulence factor. This study presents evidence for a strategy used by MERS-CoV nsp1 to inhibit host gene expression that has not been described previously for any viral protein. The present study represents a meaningful step toward a better understanding of the factors and molecular mechanisms governing the virulence and pathogenesis of MERS-CoV.