Coronaviruses using different strategies to antagonize antiviral responses and pyroptosis

Abstract

Viral infection triggers inflammasome-mediated caspase-1 activation. Nevertheless, limited understanding exists regarding how viruses use the active caspase-1 to evade host immune response. Here, we use porcine epidemic diarrhea virus (PEDV) as a model of coronaviruses (CoVs) to illustrate the intricate regulation of CoVs to combat IFN-I signaling and pyroptosis. Our findings demonstrate that PEDV infection stabilizes caspase-1 expression via papain-like protease PLP2s deubiquitinase activity and the enhanced stabilization of caspase-1 disrupts IFN-I signaling by cleaving RIG-I at D189 residue. 6-Thioguanine (6TG), a PLP2 inhibitor, plays a critical role in reversing the inhibitory effect of IFN-I via PLP2 and also inhibiting PEDV replication. Meanwhile, PLP2 can degrade GSDMD-p30 by removing its K27-linked ubiquitin chain at K275 to restrain pyroptosis. Papain-like proteases from other genera of CoVs (PDCoV and SARS-CoV-2) have the similar activity to degrade GSDMD-p30. We further demonstrate that SARS-CoV-2 N protein induced NLRP3 inflammasome activation also uses the active caspase-1 to counter IFN-I signaling by cleaving RIG-I. Therefore, our work unravels a novel antagonistic mechanism employed by CoVs to evade host antiviral response.