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However, the role of this molecular pathway during infection with the alpha-herpesvirus pseudorabies virus (PRV) remains largely elusive. Here, we report that during PRV infection, ZBP1-mediated NLRP3 inflammasome activation is inhibited by the viral tegument protein VP22, thereby facilitating viral infection. Through a combination of RNA sequencing and genetic studies, we demonstrate that PRV VP22 functions as a virus-encoded virulence factor by evading the inhibitory effects of ZBP1 on virus infection. Importantly, the replication and pathogenicity of a recombinant PRV lacking VP22 are significantly increased in ZBP1-deficient cells and mice. Mechanistically, PRV VP22 interacts with ZBP1, impeding the recruitment of receptor-interacting protein kinase 3 and Caspase-8, thereby inhibiting NLRP3 activation. Furthermore, we show that the N-terminal 1\u201350 amino acid domain of VP22 dominantly destabilizes ZBP1-mediated function. Taken together, these findings identify a functional link between PRV infection and ZBP1-mediated NLRP3 inflammatory response, providing novel insights into the pathogenesis of PRV and other herpesviruses.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Z-DNA binding protein 1 (ZBP1) functions as a pivotal innate immune sensor that regulates inflammatory cell death during viral infections. However, its role in pseudorabies virus (PRV) infection remains unknown. Here, we demonstrate that ZBP1 serves as a restrictive factor by triggering the activation of the NLR family pyrin domain-containing 3 inflammasome, a process counteracted by PRV-encoded protein VP22. Furthermore, VP22 interferes with the interaction between ZBP1 and receptor-interacting protein kinase 3\/Caspase-8, particularly through its N-terminal 1\u201350 amino acids. Importantly, deficiency in ZBP1 enhances the replication and virulence of recombinant viruses lacking VP22 or its N-terminal 1\u201350 amino acids. These findings reveal how PRV escapes ZBP1-mediated inflammatory responses during infection, potentially informing the rational design of therapeutic interventions.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01945-24","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T15:11:59Z","timestamp":1730301119000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Suppression of ZBP1-mediated NLRP3 inflammasome by the tegument protein VP22 facilitates pseudorabies virus infection"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2995-206X","authenticated-orcid":false,"given":"Zicheng","family":"Ma","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of 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