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.

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