Duck Tembusu virus NS3 protein induces apoptosis by activating the PERK/PKR pathway and mitochondrial pathway

Duck Tembusu virus (DTMUV) infection causes severe infectious diseases in poultry and can induce apoptosis in host cells. In this study, the mechanisms underlying DTMUV-induced apoptosis were investigated. First, DTMUV infection can activate the endoplasmic reticulum stress (ERS), and administration of the ERS inhibitor 4-phenylbutyric acid can protect cells from DTMUV-induced apoptosis, indicating that ERS is involved in DTMUV-induced apoptosis. Interestingly, suppression of either apoptosis or ERS led to impaired DTMUV proliferation. Then, we found that DTMUV activated three branches of unfolded protein response signaling [RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1, and activating transcription factor 6] in duck embryo fibroblasts. Further study revealed that activation of PERK-eukaryotic initiation factor 2 alpha up-regulated CCAAT/enhancer-binding protein homologous protein and DNA damage-inducible protein 34, which subsequently promoted apoptosis. Moreover, we found that among the DTMUV viral proteins, the nonstructural protein 3 (NS3) is the main inducer of apoptosis. On the one hand, the PERK/PKR pathway is involved in the NS3-mediated mitochondrial apoptosis pathway. On the other hand, NS3 interacts with voltage-dependent anion channel 2 (VDAC2) and inhibits the anti-apoptotic protein VDAC2 to induce apoptosis, which is accompanied by the depolarization of mitochondrial membrane potential and accumulation of intracellular reactive oxygen species. This study provides a theoretical basis for revealing the pathogenic mechanism of DTMUV infection and lays a foundation for finding antiviral targets.

Automated summary

In this study, the mechanism of apoptosis induced by Duck Tembusu virus (DTMUV) infection was investigated. The activation of endoplasmic reticulum stress (ERS) was found to be involved in DTMUV-induced apoptosis. The study also revealed that the nonstructural protein 3 (NS3) of DTMUV is the main inducer of apoptosis. The findings provide a theoretical basis for understanding the pathogenic mechanism of DTMUV infection and identifying potential antiviral targets.