Zhang Lujie, Gao Yanni, Zhou Haoran, Liang Xiao, Jiang Xiaolin, Gong Wenqin, Sun Yangyang, Zhang Desheng, Wang Xianwei, Nauwynck Hans, Bai Juan, Jiang Ping
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.
Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan Merelbeke, Belgium.
PLoS Pathog. 2025 Jan 27;21(1):e1012915. doi: 10.1371/journal.ppat.1012915. eCollection 2025 Jan.
The NLRP3 inflammasome is a fundamental component of the innate immune system, yet its excessive activation is intricately associated with viral pathogenesis. Porcine reproductive and respiratory syndrome virus type 2 (PRRSV-2), belonging to the family Arteriviridae, triggers dysregulated cytokine release and interstitial pneumonia, which can quickly escalate to acute respiratory distress and death. However, a mechanistic understanding of PRRSV-2 progression remains unclear. Here, we screen that PRRSV-2 nsp2 activates the NLRP3 inflammasome, thereby instigating a state of hyperinflammation. Mechanistically, PRRSV-2 nsp2 interacts with the nucleotide-binding and oligomerization (NACHT) domain of NLRP3, augmenting IKKβ recruitment to driving NLRP3 translocation to the dispersed trans-Golgi network (dTGN) for oligomerization. This process facilitates ASC polymerization, culminating in the activation of the NLRP3 inflammasome. In addition, the IKKβ-dependent NLRP3 translocation to the dTGN is pivotal for pseudorabies virus (PRV) and encephalomyocarditis virus (EMCV)-induced inflammatory responses. Collectively, these results elucidate a novel mechanism of NLRP3 inflammasome activation during PRRSV-2 infection, providing valuable insights into PRRSV-2 pathogenesis.
NLRP3炎性小体是固有免疫系统的一个基本组成部分，然而其过度激活与病毒发病机制密切相关。2型猪繁殖与呼吸综合征病毒（PRRSV-2）属于动脉炎病毒科，可引发细胞因子释放失调和间质性肺炎，进而迅速发展为急性呼吸窘迫和死亡。然而，对PRRSV-2发病机制的机械性理解仍不清楚。在此，我们筛选发现PRRSV-2的非结构蛋白2（nsp2）激活NLRP3炎性小体，从而引发一种过度炎症状态。从机制上讲，PRRSV-2的nsp2与NLRP3的核苷酸结合和寡聚化（NACHT）结构域相互作用，增加IKKβ的募集，促使NLRP3转位至分散的反式高尔基体网络（dTGN）进行寡聚化。这一过程促进凋亡相关斑点样蛋白（ASC）聚合，最终导致NLRP3炎性小体激活。此外，IKKβ依赖的NLRP3转位至dTGN对于伪狂犬病病毒（PRV）和脑心肌炎病毒（EMCV）诱导的炎症反应至关重要。总的来说，这些结果阐明了PRRSV-2感染期间NLRP3炎性小体激活的一种新机制，为PRRSV-2发病机制提供了有价值的见解。
