Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
PLoS One. 2024 Oct 31;19(10):e0312098. doi: 10.1371/journal.pone.0312098. eCollection 2024.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19). SARS-CoV-2 infection suppresses host innate immunity and impairs cell viability. Among the viral proteins, ORF6 exhibits potent interferon (IFN) antagonistic activity and cellular toxicity. It also interacts with the RNA export factor RAE1, which bridges the nuclear pore complex and nuclear export receptors, suggesting an effect on RNA export. Using the Xenopus oocyte microinjection system, I found that ORF6 blocked the export of not only mRNA but also spliceosomal U snRNA. I further demonstrated that ORF6 affects the interaction between RAE1 and nuclear export receptors and inhibits the RNA binding of RAE1. These effects of ORF6 may cumulatively block the export of several classes of RNA. I also found that ORF6 binds RNA and forms oligomers. These findings provide insights into the suppression of innate immune responses and the reduction in cell viability caused by SARS-CoV-2 infection, contributing to the development of antiviral drugs targeting ORF6.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是导致 2019 年冠状病毒病（COVID-19）的病原体。SARS-CoV-2 感染抑制宿主固有免疫并损害细胞活力。在病毒蛋白中，ORF6 具有很强的干扰素（IFN）拮抗活性和细胞毒性。它还与 RNA 输出因子 RAE1 相互作用，RAE1 桥接核孔复合体和核输出受体，表明其对 RNA 输出有影响。利用非洲爪蟾卵母细胞微量注射系统，我发现 ORF6 不仅阻断了 mRNA 的输出，还阻断了剪接体 U snRNA 的输出。我进一步证明，ORF6 影响 RAE1 与核输出受体的相互作用，并抑制 RAE1 的 RNA 结合。ORF6 的这些作用可能会累积阻断几类 RNA 的输出。我还发现 ORF6 结合 RNA 并形成寡聚物。这些发现为 SARS-CoV-2 感染引起的先天免疫反应抑制和细胞活力降低提供了深入了解，有助于开发针对 ORF6 的抗病毒药物。
