Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.
Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.
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SARS-CoV-2 ORF6 及其变异多态性对宿主反应和病毒发病机制的影响。
DOI：
10.1016/j.chom.2023.08.003
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发表时间：
2023
影响因子：
30.3
通讯作者：
Asla
中科院分区：
文献类型：
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作者：
Kehrer,Thomas;Cupic,Anastasija;Ye,Chengjin;Yildiz,Soner;Bouhaddou,Mehdi;Crossland,NicholasA;Barrall,ErikaA;Cohen,Phillip;Tseng,Anna;Çağatay,Tolga;Rathnasinghe,Raveen;Flores,Daniel;Jangra,Sonia;Alam,Fahmida;Mena,Ignacio;Asla
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）编码几种抑制宿主干扰素应答的蛋白。其中，ORF 6通过与核孔复合物组分Nup 98-Rae 1相互作用破坏核质运输来拮抗干扰素信号传导。然而，ORF 6在生理感染过程中的作用和贡献仍然未被探索。我们使用携带ORF 6缺失或功能丧失（LoF）突变的重组病毒评估了ORF 6在感染过程中的作用。ORF 6通过干扰核输入，特别是IRF和STAT转录因子的易位，在干扰素拮抗作用和病毒发病机制中起关键作用。此外，ORF 6抑制细胞mRNA输出，导致宿主细胞蛋白质组的重塑，并调节病毒蛋白质表达。有趣的是，Omicron BA.2和BA.4变体中出现的ORF 6：D 61 L突变表现出与Nup 98-Rae 1的相互作用减少，从而损害免疫逃避。我们的研究结果强调了ORF 6在拮抗先天免疫中的作用，并强调了研究SARS-CoV-2免疫逃避策略的重要性。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.