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

Yu-Wei Luo^#¹, Jiang-Peng Zhou^#¹, Hongyu Ji^#¹, Doudou Xu^#², Anqi Zheng³, Xin Wang¹, Zhizheng Dai¹, Zhicheng Luo^{1 3}, Fang Cao¹, Xing-Yue Wang³, Yunfang Bai¹, Di Chen¹, Yueming Chen³, Qi Wang⁴, Yaying Yang⁵, Xinghai Zhang⁶, Sandra Chiu^{7 8}, Xiaozhong Peng^{9 10}, Ai-Long Huang¹¹, Kai-Fu Tang¹²

Affiliations

¹ Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing, PR China.
² State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, National Center of Technology Innovation for animal model, CAMS & PUMC, Beijing, PR China.
³ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, PR China.
⁴ Department of Basic Medicine, Chongqing Medical University, Chongqing, PR China.
⁵ Department of Pathology, Molecular Medicine and Cancer Research Center, Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, PR China.
⁶ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, PR China.
⁷ Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, PR China.
⁸ Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, PR China.
⁹ State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Pathogen Infection Prevention and Control (Peking Union Medical College), Ministry of Education, National Center of Technology Innovation for animal model, CAMS & PUMC, Beijing, PR China. pengxiaozhong@pumc.edu.cn.
¹⁰ Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, PR China. pengxiaozhong@pumc.edu.cn.
¹¹ Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing, PR China. ahuang@cqmu.edu.cn.
¹² Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing, PR China. tangkaifu@cqmu.edu.cn.

^# Contributed equally.

PMID: 39138195
PMCID: PMC11322655
DOI: 10.1038/s41467-024-51192-1

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.

Nat Commun. 2024 Aug 13;15(1):6964.doi: 10.1038/s41467-024-51192-1. (IF:14.7).

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

Abstract

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