Pseudorabies virus inhibits the unfolded protein response for viral replication during the late stages of infection.

Pseudorabies virus (PRV) poses a significant threat to the global swine breeding industry and public health, but how the virus transverses the host defense systems for efficient viral replication and pathogenesis remains unclear. Here, we report that PRV could inhibit the unfolded protein response (UPR), a critical component of host innate immunity against viral infection, to promote virus replication during the late infection stages. PERK was shown phosphorylated and active in PRV-infected cells, but the subsequent events were suppressed post virus infection, such as eIF2α phosphorylation, ATF4 expression, and the formation of stress granules (SGs). In the meantime, although IRE1α was also active, its activated effector XBP1s was suppressed through downregulation of XBP1 mRNA levels and cleavage of XBP1s protein. Our findings also indicate that the Golgi apparatus, where ATF6 activation occur, was severely damaged in PRV-infected cells. Meanwhile, the downstream regulatory genes associated with the three UPR sensors, such as ERp60, CHOP, and EDEM1, remained silent in PRV-infected cells. Enhanced viral replication was observed post knockdown of UPR effectors ATF4 or XBP1, while stimulation with UPR activators inhibits virus replication. In conclusion, our findings address the critical question of how PRV regulates cellular UPR in favor of viral replication, and expand understanding of viruses mediated UPR suppression in general.