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Journal of Virology, May 2008, p. 4492-4501, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.00017-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Coronavirus Infection Modulates the Unfolded Protein Response and Mediates Sustained Translational Repression{triangledown}

John Bechill,1 Zhongbin Chen,2,3 Joseph W. Brewer,4 and Susan C. Baker1,2*

Molecular Biology Program,1 Department of Microbiology and Immunology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois,2 Department of Immunology, The Beijing Institute of Radiation Medicine, Beijing, People's Republic of China,3 Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama4

Received 3 January 2008/ Accepted 15 February 2008

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 ATF6{alpha}. However, we detected minimal downstream induction of UPR target genes, including ERdj4, ER degradation-enhancing {alpha}-mannosidase-like protein, and p58IPK, or expression of UPR reporter constructs. Translation initiation factor eIF2{alpha} 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{alpha} 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.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Loyola University Medical Center, 2160 South First Ave., Bldg. 105, Rm. 3929, Maywood, IL 60153. Phone: (708) 216-6910. Fax: (708) 216-9574. E-mail: sbaker1{at}lumc.edu

{triangledown} Published ahead of print on 27 February 2008.

Journal of Virology, May 2008, p. 4492-4501, Vol. 82, No. 9
0022-538X/08/$08.00+0     doi:10.1128/JVI.00017-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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