Sarbecovirus ORF6 proteins hamper induction of interferon signaling.
Sarbecovirus ORF6 proteins hamper induction of interferon signaling.
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DOI：
10.1016/j.celrep.2021.108916
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发表时间：
2021-03-30
期刊：
影响因子：
8.8
通讯作者：
Sato K
中科院分区：
文献类型：
--
作者：
Kimura I;Konno Y;Uriu K;Hopfensperger K;Sauter D;Nakagawa S;Sato K
开放阅读框6（ORF6）基因的存在将严重急性呼吸综合征冠状病毒（SARS - CoV）和新冠病毒（SARS - CoV - 2）等沙贝病毒与其他β冠状病毒区分开来。在此我们表明，ORF6会抑制先天免疫信号的诱导，包括在病毒感染时I型干扰素（IFN）的上调以及I型和III型干扰素信号传导。有趣的是，新冠病毒谱系的ORF6蛋白作为先天免疫的拮抗剂比SARS - CoV谱系的同源蛋白更有效。突变分析确定残基E46和Q56是新冠病毒ORF6拮抗活性的重要决定因素。此外，我们表明ORF6的抗先天免疫活性取决于其C末端区域，并且ORF6会抑制干扰素调节因子3（IRF3）的核转位。最后，我们发现了自然发生的移码/无义突变，这些突变导致约0.2%的新冠病毒分离株中ORF6发生失活截断。我们的研究结果表明，ORF6导致了在2019冠状病毒病（COVID - 19）患者中观察到的干扰素激活不良。
木村等人表明，冠状病毒的ORF6基因编码一种干扰素拮抗剂，并且是沙贝病毒（包括新冠病毒）所特有的。尽管新冠病毒ORF6的拮抗活性取决于其C末端区域，但在当前COVID - 19大流行期间分离出的所有新冠病毒基因组中，约0.2%在ORF6中含有提前终止密码子。
The presence of an ORF6 gene distinguishes sarbecoviruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 from other betacoronaviruses. Here we show that ORF6 inhibits induction of innate immune signaling, including upregulation of type I interferon (IFN) upon viral infection as well as type I and III IFN signaling. Intriguingly, ORF6 proteins from SARS-CoV-2 lineages are more efficient antagonists of innate immunity than their orthologs from SARS-CoV lineages. Mutational analyses identified residues E46 and Q56 as important determinants of the antagonistic activity of SARS-CoV-2 ORF6. Moreover, we show that the anti-innate immune activity of ORF6 depends on its C-terminal region and that ORF6 inhibits nuclear translocation of IRF3. Finally, we identify naturally occurring frameshift/nonsense mutations that result in an inactivating truncation of ORF6 in approximately 0.2% of SARS-CoV-2 isolates. Our findings suggest that ORF6 contributes to the poor IFN activation observed in individuals with coronavirus disease 2019 (COVID-19). Kimura et al. show that the coronavirus ORF6 gene encodes an interferon antagonist and is unique to sarbecoviruses, including SARS-CoV-2. Although the antagonistic activity of SARS-CoV-2 ORF6 depends on its C-terminal region, approximately 0.2% of all SARS-CoV-2 genomes isolated during the current COVID-19 pandemic harbor premature stop codons in ORF6.
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