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

Xinyu Fu; Weilv Xu; Yang Yang; Danyue Li; Wen Shi; Xinyue Li; Nan Chen; Qian Lv; Yuhua Shi; Jinxia Xu; Jidong Xu; Yuqi Yan; Fushan Shi; Xiaoliang Li

doi:10.1016/j.ijbiomac.2025.139743

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

Int J Biol Macromol. 2025 Jan 9:139743. doi: 10.1016/j.ijbiomac.2025.139743. Online ahead of print.

Authors

Xinyu Fu¹, Weilv Xu¹, Yang Yang², Danyue Li¹, Wen Shi³, Xinyue Li¹, Nan Chen¹, Qian Lv¹, Yuhua Shi¹, Jinxia Xu¹, Jidong Xu⁴, Yuqi Yan⁵, Fushan Shi⁶, Xiaoliang Li⁷

Affiliations

¹ Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China.
² Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, China.
³ College of Animal Science and Technology, Guangxi University, Nanning, China.
⁴ Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China; Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, China.
⁵ Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China; Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, China.
⁶ Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China; Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, China; Zhejiang University-Xinchang Joint Innovation Centre (TianMu Laboratory), Gaochuang Hi-Tech Park, Xinchang, China. Electronic address: [email protected].
⁷ Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China; Institute of Preventive Veterinary Medicine, Zhejiang Provincial Key Laboratory of Preventive Veterinary Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Animal Virology of Ministry of Agriculture, Center for Veterinary Sciences, Zhejiang University, Hangzhou, China; Hainan Institute of Zhejiang University, Sanya, China; Zhejiang University-Xinchang Joint Innovation Centre (TianMu Laboratory), Gaochuang Hi-Tech Park, Xinchang, China. Electronic address: [email protected].

PMID: 39798756
DOI: 10.1016/j.ijbiomac.2025.139743

Abstract

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.

Keywords: Antiviral immunity; Coronavirus; GSDMD; Papain-like protease; Type I interferon signaling.