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J. Virol. doi:10.1128/JVI.00017-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Coronavirus infection modulates the unfolded protein response and mediates sustained translational repression

Molecular Biology Program, and Department of Microbiology & Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL; Department of Immunology, The Beijing Institute of Radiation Medicine, Beijing, PRC; Department of Microbiology & Immunology, University of South Alabama, Mobile, AL

^* To whom correspondence should be addressed. Email: sbaker1{at}lumc.edu.

	Abstract

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 ATF6. However, we detected minimal downstream induction of UPR target genes including ERdj4, EDEM, and p58^IPK or expression of UPR reporter constructs. The translation initiation factor eIF2 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 eIF2 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 its potential relevance to viral mechanisms for evasion of innate defense signaling pathways during coronavirus replication is discussed.