The PERK-eIF2α branch activates the NLRP3 inflammasome through the NF-κB signaling pathway to suppress NDV replication

Viral replication in host cells commonly induces endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR) to regulate viral infection. However, the precise connection between virus-induced ER stress and the replication and pathogenesis of Newcastle disease virus (NDV) remains unclear. Here, we observed that NDV infection led to alterations in the structure of the endoplasmic reticulum in DF-1 cells and activated endoplasmic reticulum stress. Subsequent studies revealed that all three branches of the UPR were activated, including protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Treatment of DF-1 cells with endoplasmic reticulum stress inducers or inhibitors strongly inhibited or promoted viral replication. Specifically, activation of the PERK-eIF2α pathway hindered the proliferation of NDV. Furthermore, NDV infection activated the NF-κB pathway through the PERK-eIF2α axis, leading to the formation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes and the production of pro-inflammatory cytokines. Collectively, these data reveal how the UPR regulates the inflammatory response to inhibit NDV replication, which might guide the rational design of anti-NDV strategies.