PRRSV-2 nsp2 Ignites NLRP3 inflammasome through IKKβ-dependent dispersed trans-Golgi network translocation
Lujie Zhang, Yanni Gao, Haoran Zhou, Xiao Liang, Xiaolin Jiang, Wenqin Gong, Yangyang Sun, Desheng Zhang, Xianwei Wang, Hans Nauwynck, Juan Bai, Liang Li
Abstract
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.