SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia

• Published in: Nature communications Vol. 15; no. 1; pp. 6964 - 23
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 14/19; 14/63; 38/90; 49/88; 631/326/596/4130; 631/337/1427; 631/337/1645/1792; 631/337/505; 631/80/470/2284; 64/110; 64/60; 96/47; Adenosine diphosphate; Anastrozole; Animals; Aromatase; Autophagy - genetics; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - metabolism; COVID-19 - virology; Damage; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Degradation; Deoxyribonucleic acid; DNA; DNA Damage; Down-Regulation; Female; Gene expression; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; Humanities and Social Sciences; Humans; Inhibitors; Karyopherins - genetics; Karyopherins - metabolism; Lung - metabolism; Lung - pathology; Lung - virology; Male; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; N protein; Pathogenesis; Pneumonia; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Proteins; Ribonuclease III - genetics; Ribonuclease III - metabolism; Ribonucleic acid; Ribose; RNA; RNA Splicing; RNA-mediated interference; SARS-CoV-2 - genetics; Science; Science (multidisciplinary); Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Severe acute respiratory syndrome coronavirus 2; Splicing factors; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51192-1

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.