FAdV-4 induce autophagy via the endoplasmic reticulum stress-related unfolded protein response

Hydropericardium syndrome caused by the fowl adenovirus serotype 4 (FAdV-4) is prevalent disease in China with a high mortality rate. Many studies have demonstrated some viral infections to induce stress in the endoplasmic reticulum (ER). When the ER stress exceeds or persists, it activates autophagy, eventually triggering the onset of diseases. However, no report has ever stated FAdV-4 infection to induce ER stress-mediated autophagy. Previous studies have identified FAdV-4 infection in triggering autophagy in the hepatocytes; however, the underlying mechanism of this induction remains unknown. This study investigated the mechanism of ER stress-mediated autophagy induced by FAdV-4 infection. Here, ER stress was found to be triggered by FAdV-4 infection, as evident from the increased expression of the ER stress marker glucose-regulated protein 78, and the dilated morphology of the ER. Three pathways linked with the unfolded protein response (UPR) were found to be triggered in the hepatocellular carcinoma cell line, which included the PKR-like ER protein kinase (PERK), transcription factor 6, and inositol-requiring enzyme 1 (IRE1) pathways, respectively. Additionally, our results demonstrated that autophagy is involved in the PERK-eukaryotic initiation factor 2 subunit - C/EBP homologous protein and IRE1-c-Jun-N-terminal kinase pathways. Furthermore, treatment with the small interfering RNAs, or specific chemical inhibitors for the two pathways were found to reduce the interfering activity and could suppress the FAdV-4 replication. Collectively, these results developed new insight into the mechanisms of FAdV-4-induced autophagy by activating the ER stress-related UPR pathway and provided the experimental bases and novel ideas for developing antiviral drugs.