| During coronavirus replication, viral proteins induce the formation of endoplasmic reticulum (ER)-derived double membrane vesicles for RNA synthesis, and viral structural proteins assemble virions at the ER-Golgi intermediate compartment. We hypothesized the association and intense utilization of the ER during viral replication would induce the cellular unfolded protein response (UPR), a signal transduction cascade that acts to modulate translation, membrane biosynthesis and levels of ER chaperones. Here, we report that infection by the murine coronavirus, mouse hepatitis virus (MHV), triggers the proximal UPR transducers as revealed by monitoring IRE1 mediated splicing of XBP-1 mRNA and cleavage of ATF6alpha. However, we detected minimal downstream induction of UPR target genes including ERdj4, EDEM, and p58IPK or expression of UPR reporter constructs. We also found that the translation initiation factor eIF2alpha is highly phosphorylated during MHV infection and translation of cellular mRNAs is attenuated. Furthermore, we found that the critical homeostasis regulator GADD34, which recruits protein phosphatase 1 to dephosphorylate eIF2alpha during the recovery phase of the UPR, is not expressed during MHV infection. These results suggest MHV modifies the UPR by impeding induction of UPR responsive genes, thereby favoring a sustained shut-down of host cell protein synthesis while translation of viral proteins escalates. The role of this modified response and relevance to evasion of innate defense signaling pathways during viral replication is discussed. |
