The Nucleocapsid Proteins of SARS-CoV-2 and Its Close Relative Bat Coronavirus RaTG13 Are Capable of Inhibiting PKR- and RNase L-Mediated Antiviral Pathways.
The Nucleocapsid Proteins of SARS-CoV-2 and Its Close Relative Bat Coronavirus RaTG13 Are Capable of Inhibiting PKR- and RNase L-Mediated Antiviral Pathways.
复制标题
SARS-CoV-2 及其近亲蝙蝠冠状病毒 RaTG13 的核衣壳蛋白能够抑制 PKR 和 RNase L 介导的抗病毒途径。
DOI：
10.1128/spectrum.00994-23
复制
发表时间：
2023-06-15
影响因子：
3.7
通讯作者：
Cao, Jingxin
中科院分区：
文献类型：
--
作者：
LeBlanc, Kyle;Lynch, Jessie;Layne, Christine;Vendramelli, Robert;Sloan, Angela;Tailor, Nikesh;Deschambault, Yvon;Zhang, Fushun;Kobasa, Darwyn;Safronetz, David;Xiang, Yan;Cao, Jingxin
冠状病毒（CoV），包括严重急性呼吸综合征冠状病毒（SARS-CoV）、中东呼吸综合征冠状病毒（MERS-CoV）和SARS-CoV-2，产生激活PKR和OAS/RNase l等抗病毒途径的双链RNA (dsRNA)，为了在宿主中成功复制，病毒必须避开这些抗病毒途径。目前，SARS-CoV-2如何拮抗dsrna激活的抗病毒途径的机制尚不清楚。在这项研究中，我们证明了SARS-CoV-2核衣壳蛋白(N)是最丰富的病毒结构蛋白，能够结合dsRNA和磷酸化的PKR，抑制PKR和OAS/RNase L途径。蝙蝠冠状病毒（bat- cov） RaTG13的N蛋白是SARS-CoV-2的近亲，具有类似的抑制人类PKR和RNase L抗病毒途径的能力。通过诱变分析，我们发现N蛋白的c端结构域（CTD）足以结合dsRNA并抑制RNase L活性。有趣的是，虽然CTD也足以结合磷酸化的PKR，但抑制PKR抗病毒活性不仅需要CTD，还需要中央连接区（LKR）。因此，我们的研究结果表明，sars - cov - 2n蛋白能够拮抗病毒dsRNA激活的两种关键抗病毒途径，并且其抑制PKR活性需要的不仅仅是CTD介导的dsRNA结合。SARS-CoV-2的高传播性是确定2019冠状病毒病（COVID-19）大流行的重要病毒因素。为了有效传播，SARS-CoV-2必须能够有效地解除宿主的先天免疫反应。在这里，我们描述了SARS-CoV-2的核衣壳蛋白能够抑制两个关键的先天抗病毒途径PKR和OAS/RNase L.此外，与SARS-CoV-2最接近的动物冠状病毒亲戚蝙蝠冠状病毒RaTG13也可以抑制人类PKR和OAS/RNase L的抗病毒活性。因此，我们的发现对于理解COVID-19大流行的重要性是双重的。首先，sars - cov - 2n抑制先天抗病毒活性的能力可能是导致该病毒传播性和致病性的一个因素。其次，SARS-CoV-2的蝙蝠近亲具有抑制人类先天免疫的能力，因此可能有助于在人类中建立感染。本研究结果对开发新型抗病毒药物和疫苗具有重要价值。
Coronaviruses (CoVs), including severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2, produce double-stranded RNA (dsRNA) that activates antiviral pathways such as PKR and OAS/RNase L. To successfully replicate in hosts, viruses must evade such antiviral pathways. Currently, the mechanism of how SARS-CoV-2 antagonizes dsRNA-activated antiviral pathways is unknown. In this study, we demonstrate that the SARS-CoV-2 nucleocapsid (N) protein, the most abundant viral structural protein, is capable of binding to dsRNA and phosphorylated PKR, inhibiting both the PKR and OAS/RNase L pathways. The N protein of the bat coronavirus (bat-CoV) RaTG13, the closest relative of SARS-CoV-2, has a similar ability to inhibit the human PKR and RNase L antiviral pathways. Via mutagenic analysis, we found that the C-terminal domain (CTD) of the N protein is sufficient for binding dsRNA and inhibiting RNase L activity. Interestingly, while the CTD is also sufficient for binding phosphorylated PKR, the inhibition of PKR antiviral activity requires not only the CTD but also the central linker region (LKR). Thus, our findings demonstrate that the SARS-CoV-2 N protein is capable of antagonizing the two critical antiviral pathways activated by viral dsRNA and that its inhibition of PKR activities requires more than dsRNA binding mediated by the CTD. IMPORTANCE The high transmissibility of SARS-CoV-2 is an important viral factor defining the coronavirus disease 2019 (COVID-19) pandemic. To transmit efficiently, SARS-CoV-2 must be capable of disarming the innate immune response of its host efficiently. Here, we describe that the nucleocapsid protein of SARS-CoV-2 is capable of inhibiting two critical innate antiviral pathways, PKR and OAS/RNase L. Moreover, the counterpart of the closest animal coronavirus relative of SARS-CoV-2, bat-CoV RaTG13, can also inhibit human PKR and OAS/RNase L antiviral activities. Thus, the importance of our discovery for understanding the COVID-19 pandemic is 2-fold. First, the ability of SARS-CoV-2 N to inhibit innate antiviral activity is likely a factor contributing to the transmissibility and pathogenicity of the virus. Second, the bat relative of SARS-CoV-2 has the capacity to inhibit human innate immunity, which thus likely contributed to the establishment of infection in humans. The findings described in this study are valuable for developing novel antivirals and vaccines.
登录
查看更多内容
DOI：
10.3390/v13030366
发表时间：
2021-02-25
期刊：
Viruses
影响因子：
--
作者：
Etibor TA;Yamauchi Y;Amorim MJ
通讯作者：
Amorim MJ
冠状病毒内切核糖核酸酶 nsp15 抑制抗病毒应激颗粒形成，确保病毒有效复制
影响因子：
6.7
作者：
Gao B;Gong X;Fang S;Weng W;Wang H;Chu H;Sun Y;Meng C;Tan L;Song C;Qiu X;Liu W;Forlenza M;Ding C;Liao Y
通讯作者：
Liao Y
一种具有新故事的“旧”蛋白质：冠状病毒内切核糖核酸酶对于逃避宿主抗病毒防御非常重要。
影响因子：
3.7
作者：
Deng X;Baker SC
通讯作者：
Baker SC
用表达尖峰的重组ACAM2000疫苗病毒的单一免疫接种，核素蛋白可以保护仓鼠免受SARS-COV-2引起的临床疾病的侵害。
影响因子：
5.4
作者：
通讯作者：
--
影响因子：
9.2
作者：
Chiuppesi F;Nguyen VH;Park Y;Contreras H;Karpinski V;Faircloth K;Nguyen J;Kha M;Johnson D;Martinez J;Iniguez A;Zhou Q;Kaltcheva T;Frankel P;Kar S;Sharma A;Andersen H;Lewis MG;Shostak Y;Wussow F;Diamond DJ
通讯作者：
Diamond DJ