This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Xuan, B.
Right arrow Articles by Yu, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xuan, B.
Right arrow Articles by Yu, D.

 Previous Article  |  Next Article 

Journal of Virology, April 2009, p. 3463-3474, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02307-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death{triangledown}

Baoqin Xuan,{dagger} Zhikang Qian,{dagger} Emi Torigoi, and Dong Yu*

Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110

Received 4 November 2008/ Accepted 21 January 2009

The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the {alpha} subunit of eukaryotic initiation factor 2 (eIF-2{alpha}), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2{alpha} phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

* Corresponding author. Mailing address: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 362-7367. Fax: (314) 362-1232. E-mail: dongyu{at}borcim.wustl.edu

{triangledown} Published ahead of print on 4 February 2009.

{dagger} B.X. and Z.Q. contributed equally to this study.

Journal of Virology, April 2009, p. 3463-3474, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02307-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Buchkovich, N. J., Maguire, T. G., Paton, A. W., Paton, J. C., Alwine, J. C. (2009). The Endoplasmic Reticulum Chaperone BiP/GRP78 Is Important in the Structure and Function of the Human Cytomegalovirus Assembly Compartment. J. Virol. 83: 11421-11428 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»