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The nonstructural protein 5 of coronaviruses antagonizes GSDMD-mediated pyroptosis by cleaving and inactivating its pore-forming p30 fragment

By Fushan Shi, Qian Lv, Tingjun Wang, Jidong Xu, Wei Xu, Yuhua Shi, Xinyu Fu, Tianming Yang, Yang Yang, Lenan Zhuang, Weihuan Fang, Jinyan Gu, Xiaoliang Li

Posted 24 Feb 2021
bioRxiv DOI: 10.1101/2021.02.23.432418

Coronaviruses (CoV) are a family of RNA viruses that typically cause respiratory, enteric and hepatic diseases in animals and humans. Here, we used porcine epidemic diarrhea virus (PEDV) as a model of coronaviruses (CoVs) to illustrate the reciprocal regulation between CoVs infection and pyroptosis. For the first time, we clarified the molecular mechanism of porcine Gasdermin D (pGSDMD)-mediated pyroptosis and demonstrated that amino acids T239 and F240 within pGSDMD-p30 are critical for pyroptosis. Furthermore, 3C-like protease Nsp5 from SARS-CoV-2, MERS-CoV, PDCoV and PEDV can cleave human/porcine GSDMD at the Q193-G194 junction upstream of the caspase-1 cleavage site to produce two fragments which fail to trigger pyroptosis or inhibit viral replication. Thus, we provide clear evidence that coronoviruses may utilize viral Nsp5-GSDMD pathway to help their host cells escaping from pyroptosis, protecting the replication of the virus during the initial period, which suggest an important strategy for coronoviruses infection and sustain.

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