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- Title
SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia.
- Authors
Luo, Yu-Wei; Zhou, Jiang-Peng; Ji, Hongyu; Xu, Doudou; Zheng, Anqi; Wang, Xin; Dai, Zhizheng; Luo, Zhicheng; Cao, Fang; Wang, Xing-Yue; Bai, Yunfang; Chen, Di; Chen, Yueming; Wang, Qi; Yang, Yaying; Zhang, Xinghai; Chiu, Sandra; Peng, Xiaozhong; Huang, Ai-Long; Tang, Kai-Fu
- 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. Here, the authors provide evidence that SARS-CoV-2 N protein leads to autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inducing DNA damage and proteotoxic stress, eventually causing pneumonia. The small-molecule drug PJ34 or anastrozole alleviates N protein-induced pneumonia.
- Subjects
SARS-CoV-2; COVID-19; RNA splicing; DNA damage; AROMATASE inhibitors; POLY ADP ribose
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-51192-1