SARS-CoV-2 infection triggers widespread host mRNA decay leading to an mRNA export block.
SARS-CoV-2 infection triggers widespread host mRNA decay leading to an mRNA export block.
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SARS-COV-2感染触发了广泛的宿主mRNA衰变，导致mRNA导出块。
DOI：
10.1261/rna.078923.121
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Parker R
中科院分区：
文献类型：
--
作者：
Burke JM;St Clair LA;Perera R;Parker R
干扰素（IFN）基因的转录诱导是哺乳动物抗病毒反应的一个关键特征，限制了病毒的复制和传播。由SARS-CoV-2引起的严重COVID-19疾病的一个标志是患者血清中IFN蛋白的低存在，尽管IFN编码mRNA水平升高，表明IFN蛋白产生的转录后抑制。在这里，我们进行了单分子RNA可视化，以检查在SARS-CoV-2感染宿主mRNA的表达和定位。我们的数据表明，I型和III型IFN mRNA的生物合成在SARS-CoV-2感染期间在多个步骤中被抑制。首先，干扰素调节因子3（IRF 3）转录因子易位到细胞核是有限的响应SARS-CoV-2，表明SARS-CoV-2抑制RLR-MAVS信号转导，从而削弱IFN基因的转录诱导。其次，我们观察到IFN mRNA主要定位于大多数SARS-CoV-2感染细胞的转录位点，这表明SARS-CoV-2抑制IFN mRNA从其转录位点的释放和/或在离开转录位点时触发细胞核中IFN mRNA的衰变。最后，在SARS-CoV-2感染期间，IFN mRNA的核质转运受到抑制，我们认为这是SARS-CoV-2复制早期宿主细胞质基础mRNA被SARS-CoV-2 Nsp 1蛋白以及宿主抗病毒核糖核酸内切酶RNase L广泛降解的结果。重要的是，如果IFN mRNA到达细胞质，它们可以逃避SARS-CoV-2介导的降解，使得mRNA输出的拯救成为促进对SARS-CoV-2的免疫应答的可行手段。
The transcriptional induction of interferon (IFN) genes is a key feature of the mammalian antiviral response that limits viral replication and dissemination. A hallmark of severe COVID-19 disease caused by SARS-CoV-2 is the low presence of IFN proteins in patient serum despite elevated levels of IFN-encoding mRNAs, indicative of post-transcriptional inhibition of IFN protein production. Here, we performed single-molecule RNA visualization to examine the expression and localization of host mRNAs during SARS-CoV-2 infection. Our data show that the biogenesis of type I and type III IFN mRNAs is inhibited at multiple steps during SARS-CoV-2 infection. First, translocation of the interferon regulatory factor 3 (IRF3) transcription factor to the nucleus is limited in response to SARS-CoV-2, indicating that SARS-CoV-2 inhibits RLR-MAVS signaling and thus weakens transcriptional induction of IFN genes. Second, we observed that IFN mRNAs primarily localize to the site of transcription in most SARS-CoV-2 infected cells, suggesting that SARS-CoV-2 either inhibits the release of IFN mRNAs from their sites of transcription and/or triggers decay of IFN mRNAs in the nucleus upon exiting the site of transcription. Lastly, nuclear-cytoplasmic transport of IFN mRNAs is inhibited during SARS-CoV-2 infection, which we propose is a consequence of widespread degradation of host cytoplasmic basal mRNAs in the early stages of SARS-CoV-2 replication by the SARS-CoV-2 Nsp1 protein, as well as the host antiviral endoribonuclease, RNase L. Importantly, IFN mRNAs can escape SARS-CoV-2-mediated degradation if they reach the cytoplasm, making rescue of mRNA export a viable means for promoting the immune response to SARS-CoV-2.
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影响因子：
7
作者：
Yang, E;van Nimwegen, E;Darnell, JE
通讯作者：
Darnell, JE
DOI：
10.1073/pnas.0603144103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Kamitani, Wataru;Narayanan, Krishna;Makino, Shinji
通讯作者：
Makino, Shinji
影响因子：
24.8
作者：
Lee, Jeong Seok;Park, Seongwan;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
DOI：
10.1074/jbc.m708375200
发表时间：
2008-02-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bhardwaj K;Palaninathan S;Alcantara JMO;Li Yi L;Guarino L;Sacchettini JC;Kao CC
通讯作者：
Kao CC
影响因子：
13.6
作者：
Burke JM;Gilchrist AR;Sawyer SL;Parker R
通讯作者：
Parker R