Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression.
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 that 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 the 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 the IRE1-mediated splicing of XBP-1 mRNA and the cleavage of ATF6alpha. However, we detected minimal downstream induction of UPR target genes, including ERdj4, ER degradation-enhancing alpha-mannosidase-like protein, and p58(IPK), or expression of UPR reporter constructs. 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 that MHV modifies the UPR by impeding the induction of UPR-responsive genes, thereby favoring a sustained shutdown of the synthesis of host cell proteins while the translation of viral proteins escalates. The role of this modified response and its potential relevance to viral mechanisms for the evasion of innate defense signaling pathways during coronavirus replication are discussed.
Bechill
John
J
Department of Microbiology and Immunology, Loyola University Medical Center, 2160 South First Ave., Bldg. 105, Rm. 3929, Maywood, IL 60153, USA.
Chen
Zhongbin
Z
Brewer
Joseph W
JW
Baker
Susan C
SC
D000818:Animals; D018352:Coronavirus Infections / Q000821:virology*; D005786:Gene Expression Regulation; D051379:Mice; D006517:Murine hepatitis virus / Q000502:physiology*; D014176:Protein Biosynthesis; D017510:Protein Folding; D015398:Signal Transduction; D014779:Virus Replication