Diverse strategies utilized by coronaviruses to evade antiviral responses and suppress pyroptosis.

Viral infections trigger 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 PLP2's deubiquitinase activity. This stabilization of caspase-1 disrupts IFN-I signaling by cleaving RIG-I at the D189 residue. Furthermore, we demonstrate that 6-thioguanine (6TG), a PLP2 inhibitor, reverses the inhibitory effect on IFN-I signaling mediated by PLP2 and significantly reduces PEDV replication. Additionally, PLP2 degrades 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.