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

Nature communications (2021-08-04)
Pan Pan, Miaomiao Shen, Zhenyang Yu, Weiwei Ge, Keli Chen, Mingfu Tian, Feng Xiao, Zhenwei Wang, Jun Wang, Yaling Jia, Wenbiao Wang, Pin Wan, Jing Zhang, Weijie Chen, Zhiwei Lei, Xin Chen, Zhen Luo, Qiwei Zhang, Meng Xu, Geng Li, Yongkui Li, Jianguo Wu
ZUSAMMENFASSUNG

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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