PERK-mediated eIF2α phosphorylation suppresses porcine epidemic diarrhea virus replication by attenuating global protein synthesis and inducing IFN-Ⅰ production.

Porcine epidemic diarrhea virus (PEDV) is one of the most important porcine pathogens for which no preventive and antiviral treatment measures are available. A pervious study revealed that the unfolded protein response (UPR) induced by endoplasmic reticulum (ER) stress can be utilized to inhibit PEDV replication. Here, we demonstrated that the UPR suppresses the replication of multiple genotypes of PEDV in both Vero and swine testis (ST) cells, primarily through activation of the PERK-eIF2α branch among the three UPR pathways. The PERK-eIF2α pathway inducers CCT020312 and salubrinal efficiently inhibited the replication of multiple genotypes of PEDV in both Vero and ST cells, whereas the inhibitor AMG PERK 44 promoted PEDV replication. Furthermore, we found that PERK-eIF2α arm-mediated inhibition of PEDV replication is caused by phosphorylated eIF2α-induced attenuation of global protein translation. Additionally, phosphorylated eIF2α promotes NF-κB signaling activation and facilitates to the production of IFN-Ⅰ, eliciting innate immunity to suppress viral replication. These data show that PERK-eIF2α pathway dampens the replication of multiple genotypes of PEDV, suggesting that this target may be exploited to develop as a broad-spectrum anti-PEDV drugs.