The glycoprotein 5 of porcine reproductive and respiratory syndrome virus stimulates mitochondrial ROS to facilitate viral replication

作者：Shuang Zhang, Lei Zeng, Bing-Qian Su, Guo‐Yu Yang, Jiang Wang, Sheng‐Li Ming, Bei‐Bei Chu · 发表于：mBio · 年份：2023 · DOI：10.1128/mbio.02651-23 · 被引用次数：39 · 研究领域：Animal Virus Infections Studies、Virus-based gene therapy research、Viral gastroenteritis research and epidemiology

ABSTRACT Viruses have evolved sophisticated mechanisms to manipulate host cell organelles to serve as niches for persistence and proliferation. In the present study, we aimed to investigate the role of cellular organelles in the replication of porcine reproductive and respiratory syndrome virus (PRRSV). We found that the morphology of mitochondria and the endoplasmic reticulum (ER) were both altered, and the contact between these two organelles was enhanced during PRRSV infection. By the overexpression of PRRSV-encoded open reading frames, we identified that only glycoprotein 5 (GP5) was essential for ER-mitochondria contact. Further investigation revealed that GP5 interacted with the ER inositol 1,4,5-triphosphate receptor (IP3R) and the mitochondrial voltage-dependent anion channel (VDAC1) to promote the Ca 2+ efflux from ER into mitochondria. Excessive mitochondrial Ca 2+ uptake resulted in mitochondrial dysfunction and substantial mitochondrial reactive oxygen species (mROS) production. Elevated mROS activated autophagy through the AMPK/mROR/ULK1 axis to facilitate PRRSV replication. GP5-induced mROS also triggered the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Inhibition of autophagy augmented NLRP3 inflammasome activation and exhibited an anti-PRRSV effect, suggesting autophagy counteracted the NLRP3-mediated innate immune response. Overall, our findings highlighted the importance of cellular organelles in virus-host interactions an...