Suppression of ZBP1-mediated NLRP3 inflammasome by the tegument protein VP22 facilitates pseudorabies virus infection
Zicheng Ma,
Depeng Liu,
Wandi Cao,
Lei Guo,
Kesen Liu,
Juan Bai,
Xingyi Li,
Ping Jiang,
Xing Liu
Affiliations
Zicheng Ma
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Depeng Liu
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Wandi Cao
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Lei Guo
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Kesen Liu
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Juan Bai
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Xingyi Li
School of Computer Science, Northwestern Polytechnical University, Xi'an, Shanxi, China
Ping Jiang
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
Xing Liu
Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
ABSTRACT The interaction between Z-DNA binding protein 1 (ZBP1) and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome has been uncovered in several viral infections. 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 1–50 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.IMPORTANCEZ-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 1–50 amino acids. Importantly, deficiency in ZBP1 enhances the replication and virulence of recombinant viruses lacking VP22 or its N-terminal 1–50 amino acids. These findings reveal how PRV escapes ZBP1-mediated inflammatory responses during infection, potentially informing the rational design of therapeutic interventions.
