PDF(Pubmed)
Abstract：
Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia\'s severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.
摘要：
尽管RNAi和RNA剪接机制参与调节严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的复制，它们在2019年冠状病毒病(COVID-19)发病机制中的确切作用仍不清楚。在这里，我们显示RNAi成分(Dicer和XPO5)和剪接因子(SRSF3和hnRNPA3)表达减少与COVID-19严重程度增加相关。SARS-CoV-2N蛋白诱导Dicer自噬降解,XPO5、SRSF3和hnRNPA3抑制miRNA生物发生和RNA剪接并触发DNA损伤,蛋白毒性应激,和肺炎。Dicer,XPO5、SRSF3和hnRNPA3敲低增加，虽然它们的过度表达减少，N蛋白诱导的肺炎的严重程度。年龄较大的小鼠表现出较低的Dicer表达，XPO5，SRSF3和hnRNPA3在其肺组织中表现出比年轻小鼠更严重的N蛋白诱导的肺炎。PJ34，一种聚（ADP-核糖）聚合酶抑制剂，或者阿那曲唑,芳香化酶抑制剂,通过恢复Dicer改善N蛋白或SARS-CoV-2引起的肺炎，XPO5、SRSF3和hnRNPA3表达。这些发现将有助于开发SARS-CoV-2相关肺炎的改进治疗方法。
