tetano
Editor, Senior Moderator
Nat Commun
. 2024 Aug 13;15(1):6964.
doi: 10.1038/s41467-024-51192-1. SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia
Yu-Wei Luo[SUP] #[/SUP][SUP] 1 [/SUP], Jiang-Peng Zhou[SUP] #[/SUP][SUP] 1 [/SUP], Hongyu Ji[SUP] #[/SUP][SUP] 1 [/SUP], Doudou Xu[SUP] #[/SUP][SUP] 2 [/SUP], Anqi Zheng[SUP] 3 [/SUP], Xin Wang[SUP] 1 [/SUP], Zhizheng Dai[SUP] 1 [/SUP], Zhicheng Luo[SUP] 1 3 [/SUP], Fang Cao[SUP] 1 [/SUP], Xing-Yue Wang[SUP] 3 [/SUP], Yunfang Bai[SUP] 1 [/SUP], Di Chen[SUP] 1 [/SUP], Yueming Chen[SUP] 3 [/SUP], Qi Wang[SUP] 4 [/SUP], Yaying Yang[SUP] 5 [/SUP], Xinghai Zhang[SUP] 6 [/SUP], Sandra Chiu[SUP] 7 8 [/SUP], Xiaozhong Peng[SUP] 9 10 [/SUP], Ai-Long Huang[SUP] 11 [/SUP], Kai-Fu Tang[SUP] 12 [/SUP]
Affiliations
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.
. 2024 Aug 13;15(1):6964.
doi: 10.1038/s41467-024-51192-1. SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia
Yu-Wei Luo[SUP] #[/SUP][SUP] 1 [/SUP], Jiang-Peng Zhou[SUP] #[/SUP][SUP] 1 [/SUP], Hongyu Ji[SUP] #[/SUP][SUP] 1 [/SUP], Doudou Xu[SUP] #[/SUP][SUP] 2 [/SUP], Anqi Zheng[SUP] 3 [/SUP], Xin Wang[SUP] 1 [/SUP], Zhizheng Dai[SUP] 1 [/SUP], Zhicheng Luo[SUP] 1 3 [/SUP], Fang Cao[SUP] 1 [/SUP], Xing-Yue Wang[SUP] 3 [/SUP], Yunfang Bai[SUP] 1 [/SUP], Di Chen[SUP] 1 [/SUP], Yueming Chen[SUP] 3 [/SUP], Qi Wang[SUP] 4 [/SUP], Yaying Yang[SUP] 5 [/SUP], Xinghai Zhang[SUP] 6 [/SUP], Sandra Chiu[SUP] 7 8 [/SUP], Xiaozhong Peng[SUP] 9 10 [/SUP], Ai-Long Huang[SUP] 11 [/SUP], Kai-Fu Tang[SUP] 12 [/SUP]
Affiliations
- PMID: 39138195
- PMCID: PMC11322655
- 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.