SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia
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.
Authors
- Yuwei Luo (ORCID: https://orcid.org/0009-0008-9094-8896)
- Zhizheng Dai
- Xiaozhong Peng (ORCID: https://orcid.org/0000-0002-9592-9554)
- Xingyue Wang (ORCID: https://orcid.org/0000-0003-1177-539X)
- Kai‐Fu Tang (ORCID: https://orcid.org/0000-0002-6892-1207)
- Ailong Huang (ORCID: https://orcid.org/0000-0003-0148-7423)
- Sandra Chiu (ORCID: https://orcid.org/0000-0001-9034-5755)
- Yaying Yang (ORCID: https://orcid.org/0000-0002-8901-3427)
- Anqi Zheng (ORCID: https://orcid.org/0000-0003-2976-5819)
- Zhicheng Luo (ORCID: https://orcid.org/0000-0002-8182-0523)
- Di Chen (ORCID: https://orcid.org/0000-0002-2186-7717)
- Fang Cao (ORCID: https://orcid.org/0000-0001-6506-9015)
- Doudou Xu
- Xinghai Zhang
- Yueming Chen
- Hongyu Ji
- Yunfang Bai
- Jiang-Peng Zhou
- Xin Wang (ORCID: https://orcid.org/0009-0004-2370-0779)
- Qi Wang (ORCID: https://orcid.org/0000-0002-1556-2167)
Institutions
- University of Science and Technology of China (CN)
- Anhui University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wenzhou Medical University (CN)
- First Affiliated Hospital of Wenzhou Medical University (CN)
- Wuhan Institute of Virology (CN)
- Institute of Laboratory Animal Science (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1038/s41467-024-51192-1
- Citations
- 8
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.87