The Molecular Mechanism Of Transmissible Gastroenteritis Virus Replication Regulated By The ER Stress

Coronavirus replication is closely associated with the endoplasmic reticulum(ER),the primary cellular organelle for protein synthesis,folding,and modification.ER stress is a common consequence in coronavirus-infected cells.However,how the virus-induced ER stress influences coronavirus replication and pathogenesis remains controversial.Here,we demonstrated that infection with the alphacoronavirus transmissible gastroenteritis virus(TGEV)induced ER stress and triggered the unfolded protein response(UPR)in vitro and in vivo,and ER stress negatively regulated TGEV replication in vitro.Although TGEV infection activated all three UPR pathways(ATF6,IRE1,and PERK),the virus-triggered UPR suppressed TGEV replication in both ST and IPEC-J2 cells primarily through activation of the PERK-eIF2a axis,as shown by functional studies with siRNA or specific chemical inhibitors.Moreover,we demonstrated that PERK-eIF2a axis-mediated inhibition of TGEV replication is through phosphorylated eIF2a-induced overall attenuation of protein translation.In addition to direct inhibition of viral production,the PERK-eIF2a pathway activated NF-?B and then facilitated type I IFN production,resulting in TGEV suppression.Taken together,our results suggest that the TGEV-triggered PERK-eIF2a pathway negatively regulates TGEV replication and represents a vital aspect of host innate responses to invading pathogens.