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

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  • 作者: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
  • 期刊:Nature Communications
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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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