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

• Published in: Nature communications Vol. 12; no. 1; p. 4664
• Main Authors: Pan, Pan, Shen, Miaomiao, Yu, Zhenyang, Ge, Weiwei, Chen, Keli, Tian, Mingfu, Xiao, Feng, Wang, Zhenwei, Wang, Jun, Jia, Yaling, Wang, Wenbiao, Wan, Pin, Zhang, Jing, Chen, Weijie, Lei, Zhiwei, Chen, Xin, Luo, Zhen, Zhang, Qiwei, Xu, Meng, Li, Geng, Li, Yongkui, Wu, Jianguo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-08-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/21; 13/51; 13/89; 14/19; 38; 42; 45; 45/111; 631/250/254; 631/250/256/2177; 631/326/596/2553; 82/51; 96/95; Animal models; Animals; Caspase-1; Cells, Cultured; Coronavirus Nucleocapsid Proteins - metabolism; Coronaviruses; COVID-19; COVID-19 - metabolism; COVID-19 - virology; Cytokine storm; Cytokines; Cytokines - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; IL-1β; Infections; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Inflammation - metabolism; Inhibitors; Interleukin 6; Lung Injury - genetics; Lung Injury - metabolism; Lungs; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; N protein; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Phosphoproteins - metabolism; Protein Binding; Proteins; SARS-CoV-2 - metabolism; SARS-CoV-2 - physiology; Science; Science (multidisciplinary); Sepsis; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; THP-1 Cells; Viral diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25015-6

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.
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.