期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25015-6
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资金
- National Natural Science Foundation of China [81730061]
- Guangdong Province Pearl River Talent Plan Innovation and Entrepreneurship Team Project [2017ZT07Y580]
- China Postdoctoral Science Foundation [2020M683177, 2020T130046ZX]
- Natural Science Foundation of Guangdong Province general program [2020A1515010369]
- Fundamental Research Funds for the Central Universities [21620401, 11620301]
This study reveals a unique mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation, leading to excessive inflammatory responses. The interaction between N protein and NLRP3 enhances the assembly of the NLRP3 inflammasome by facilitating binding with ASC.
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-1 beta 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. SARS-CoV-2 infection has been shown to drive NLRP3 inflammasome activation and thereby cytokine storm, but how it does so is unclear. Here the authors show that the viral N protein can bind to NLRP3, resulting in enhanced interaction with ASC and thereby with the NLRP3 inflammasome.
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