SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

  • Nat Commun. 2021 Aug 2;12(1):4664. doi: 10.1038/s41467-021-25015-6.
Pan Pan  #  1  2 ,  Miaomiao Shen  #  3 ,  Zhenyang Yu  #  3 ,  Weiwei Ge  3 ,  Keli Chen  3 ,  Mingfu Tian  2  3 ,  Feng Xiao  3 ,  Zhenwei Wang  2 ,  Jun Wang  4 ,  Yaling Jia  2 ,  Wenbiao Wang  2 ,  Pin Wan  2 ,  Jing Zhang  2 ,  Weijie Chen  2 ,  Zhiwei Lei  2 ,  Xin Chen  2 ,  Zhen Luo  2  5 ,  Qiwei Zhang  2  5 ,  Meng Xu  1 ,  Geng Li  6  7 ,  Yongkui Li  8  9 ,  Jianguo Wu  10  11  12  13
Affiliations
  • 1. The First Affiliated Hospital of Jinan University, Guangzhou, China.
  • 2. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China.
  • 3. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
  • 4. The Affiliated ShunDe Hospital of Jinan University, Foshan, China.
  • 5. Foshan Institute of Medical Microbiology, Foshan, China.
  • 6. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China. [email protected].
  • 7. Foshan Institute of Medical Microbiology, Foshan, China. [email protected].
  • 8. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China. [email protected].
  • 9. Foshan Institute of Medical Microbiology, Foshan, China. [email protected].
  • 10. The First Affiliated Hospital of Jinan University, Guangzhou, China. [email protected].
  • 11. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China. [email protected].
  • 12. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China. [email protected].
  • 13. Foshan Institute of Medical Microbiology, Foshan, China. [email protected].
  • # Contributed equally.
PMID: 34341353 DOI: 10.1038/s41467-021-25015-6
Abstract

Excessive inflammatory responses induced upon SARS-CoV-2 Infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 Infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of Caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.