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

Replication of a Cytopathic Strain of Bovine Viral Diarrhea Virus Activates PERK and Induces Endoplasmic Reticulum Stress-Mediated Apoptosis of MDBK Cells

Department of Biochemistry and Molecular Pharmacology, The Jefferson Center for Biomedical Research, Thomas Jefferson University, Doylestown, Pennsylvania 18901

Received 10 April 2002/ Accepted 19 June 2002

Endoplasmic reticulum (ER) stress signaling is an adaptive cellular response to the loss of ER Ca²⁺ homeostasis and/or the accumulation of misfolded, unassembled, or aggregated proteins in the ER lumen. ER stress-activated signaling pathways regulate protein synthesis initiation and can also trigger apoptosis through the ER-associated caspase 12. Viruses that utilize the host cell ER as an integral part of their life cycle would be predicted to cause some level of ER stress. Bovine viral diarrhea virus (BVDV) is a positive-stranded RNA virus of the Flaviviridae family. BVDV and related flaviviruses use the host ER as the primary site of envelope glycoprotein biogenesis, genomic replication, and particle assembly. We are using a cytopathic strain of BVDV (cpBVDV) that causes cellular apoptosis as a model system to determine how virus-induced ER stress contributes to pathogenesis. We show that, in a natural infection of MDBK cells, cpBVDV activates the ER transmembrane kinase PERK (PKR-like ER kinase) and causes hyperphosphorylation of the translation initiation factor eIF2, consistent with the induction of an ER stress response. Additionally, we show that initiation of cellular apoptosis correlates with downregulation of the antiapoptotic Bcl-2 protein, induced expression of caspase 12, and a decrease in intracellular glutathione levels. Defining the molecular stress pathways leading to cpBVDV-induced apoptosis provides the basis to study how other ER-tropic viruses, such as hepatitis C and B viruses, modulate the host cell ER stress response during the course of persistent infection.

This article has been cited by other articles:

• Nishitoh, H., Kadowaki, H., Nagai, A., Maruyama, T., Yokota, T., Fukutomi, H., Noguchi, T., Matsuzawa, A., Takeda, K., Ichijo, H. (2008). ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 22: 1451-1464 [Abstract] [Full Text]  
• Parikh, B. A., Tortora, A., Li, X.-P., Tumer, N. E. (2008). Ricin Inhibits Activation of the Unfolded Protein Response by Preventing Splicing of the HAC1 mRNA. J. Biol. Chem. 283: 6145-6153 [Abstract] [Full Text]  
• Medigeshi, G. R., Lancaster, A. M., Hirsch, A. J., Briese, T., Lipkin, W. I., DeFilippis, V., Fruh, K., Mason, P. W., Nikolich-Zugich, J., Nelson, J. A. (2007). West Nile Virus Infection Activates the Unfolded Protein Response, Leading to CHOP Induction and Apoptosis. J. Virol. 81: 10849-10860 [Abstract] [Full Text]  
• Ambagala, A. P. N., Cohen, J. I. (2007). Varicella-Zoster Virus IE63, a Major Viral Latency Protein, Is Required To Inhibit the Alpha Interferon-Induced Antiviral Response. J. Virol. 81: 7844-7851 [Abstract] [Full Text]  
• Mulvey, M., Arias, C., Mohr, I. (2007). Maintenance of Endoplasmic Reticulum (ER) Homeostasis in Herpes Simplex Virus Type 1-Infected Cells through the Association of a Viral Glycoprotein with PERK, a Cellular ER Stress Sensor. J. Virol. 81: 3377-3390 [Abstract] [Full Text]  
• Goodman, A. G., Smith, J. A., Balachandran, S., Perwitasari, O., Proll, S. C., Thomas, M. J., Korth, M. J., Barber, G. N., Schiff, L. A., Katze, M. G. (2007). The Cellular Protein P58IPK Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism. J. Virol. 81: 2221-2230 [Abstract] [Full Text]  
• Martin, G., Cagnon, N., Sabido, O., Sion, B., Grizard, G., Durand, P., Levy, R. (2007). Kinetics of occurrence of some features of apoptosis during the cryopreservation process of bovine spermatozoa. Hum Reprod 22: 380-388 [Abstract] [Full Text]  
• Zahn, R. C., Schelp, I., Utermohlen, O., von Laer, D. (2007). A-to-G Hypermutation in the Genome of Lymphocytic Choriomeningitis Virus. J. Virol. 81: 457-464 [Abstract] [Full Text]  
• Yu, C.-Y., Hsu, Y.-W., Liao, C.-L., Lin, Y.-L. (2006). Flavivirus Infection Activates the XBP1 Pathway of the Unfolded Protein Response To Cope with Endoplasmic Reticulum Stress. J. Virol. 80: 11868-11880 [Abstract] [Full Text]  
• Yamane, D., Kato, K., Tohya, Y., Akashi, H. (2006). The double-stranded RNA-induced apoptosis pathway is involved in the cytopathogenicity of cytopathogenic Bovine viral diarrhea virus.. J. Gen. Virol. 87: 2961-2970 [Abstract] [Full Text]  
• Williams, B. L., Lipkin, W. I. (2006). Endoplasmic reticulum stress and neurodegeneration in rats neonatally infected with borna disease virus.. J. Virol. 80: 8613-8626 [Abstract] [Full Text]  
• Chan, C.-P., Siu, K.-L., Chin, K.-T., Yuen, K.-Y., Zheng, B., Jin, D.-Y. (2006). Modulation of the unfolded protein response by the severe acute respiratory syndrome coronavirus spike protein.. J. Virol. 80: 9279-9287 [Abstract] [Full Text]  
• Mulvey, M., Arias, C., Mohr, I. (2006). Resistance of mRNA translation to acute endoplasmic reticulum stress-inducing agents in herpes simplex virus type 1-infected cells requires multiple virus-encoded functions.. J. Virol. 80: 7354-7363 [Abstract] [Full Text]  
• Abdelrahim, M., Newman, K., Vanderlaag, K., Samudio, I., Safe, S. (2006). 3,3'-Diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis 27: 717-728 [Abstract] [Full Text]  
• Isler, J. A., Maguire, T. G., Alwine, J. C. (2005). Production of Infectious Human Cytomegalovirus Virions Is Inhibited by Drugs That Disrupt Calcium Homeostasis in the Endoplasmic Reticulum. J. Virol. 79: 15388-15397 [Abstract] [Full Text]  
• Isler, J. A., Skalet, A. H., Alwine, J. C. (2005). Human Cytomegalovirus Infection Activates and Regulates the Unfolded Protein Response. J. Virol. 79: 6890-6899 [Abstract] [Full Text]  
• Cheng, G., Feng, Z., He, B. (2005). Herpes Simplex Virus 1 Infection Activates the Endoplasmic Reticulum Resident Kinase PERK and Mediates eIF-2{alpha} Dephosphorylation by the {gamma}134.5 Protein. J. Virol. 79: 1379-1388 [Abstract] [Full Text]  
• Ryman, K. D., Meier, K. C., Nangle, E. M., Ragsdale, S. L., Korneeva, N. L., Rhoads, R. E., MacDonald, M. R., Klimstra, W. B. (2005). Sindbis Virus Translation Is Inhibited by a PKR/RNase L-Independent Effector Induced by Alpha/Beta Interferon Priming of Dendritic Cells. J. Virol. 79: 1487-1499 [Abstract] [Full Text]  
• Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H. P., Ron, D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18: 3066-3077 [Abstract] [Full Text]  
• Reboredo, M., Greaves, R. F., Hahn, G. (2004). Human cytomegalovirus proteins encoded by UL37 exon 1 protect infected fibroblasts against virus-induced apoptosis and are required for efficient virus replication. J. Gen. Virol. 85: 3555-3567 [Abstract] [Full Text]  
• Baltzis, D., Qu, L.-K., Papadopoulou, S., Blais, J. D., Bell, J. C., Sonenberg, N., Koromilas, A. E. (2004). Resistance to Vesicular Stomatitis Virus Infection Requires a Functional Cross Talk between the Eukaryotic Translation Initiation Factor 2{alpha} Kinases PERK and PKR. J. Virol. 78: 12747-12761 [Abstract] [Full Text]  
• Netherton, C. L., Parsley, J. C., Wileman, T. (2004). African Swine Fever Virus Inhibits Induction of the Stress-Induced Proapoptotic Transcription Factor CHOP/GADD153. J. Virol. 78: 10825-10828 [Abstract] [Full Text]  
• Sun, M., Rothermel, T. A., Shuman, L., Aligo, J. A., Xu, S., Lin, Y., Lamb, R. A., He, B. (2004). Conserved Cysteine-Rich Domain of Paramyxovirus Simian Virus 5 V Protein Plays an Important Role in Blocking Apoptosis. J. Virol. 78: 5068-5078 [Abstract] [Full Text]  
• Tardif, K. D., Mori, K., Kaufman, R. J., Siddiqui, A. (2004). Hepatitis C Virus Suppresses the IRE1-XBP1 Pathway of the Unfolded Protein Response. J. Biol. Chem. 279: 17158-17164 [Abstract] [Full Text]  
• SZEGEZDI, E., FITZGERALD, U., SAMALI, A. (2003). Caspase-12 and ER-Stress-Mediated Apoptosis: The Story So Far. Ann. N. Y. Acad. Sci. 1010: 186-194 [Abstract] [Full Text]  
• Dimcheff, D. E., Askovic, S., Baker, A. H., Johnson-Fowler, C., Portis, J. L. (2003). Endoplasmic Reticulum Stress Is a Determinant of Retrovirus-Induced Spongiform Neurodegeneration. J. Virol. 77: 12617-12629 [Abstract] [Full Text]  
• Robbins, M. A., Maksumova, L., Pocock, E., Chantler, J. K. (2003). Nuclear Factor-{kappa}B Translocation Mediates Double-Stranded Ribonucleic Acid-Induced NIT-1 {beta}-Cell Apoptosis and Up-Regulates Caspase-12 and Tumor Necrosis Factor Receptor-Associated Ligand (TRAIL). Endocrinology 144: 4616-4625 [Abstract] [Full Text]  
• Kalai, M., Lamkanfi, M., Denecker, G., Boogmans, M., Lippens, S., Meeus, A., Declercq, W., Vandenabeele, P. (2003). Regulation of the expression and processing of caspase-12. J. Cell Biol. 162: 457-467 [Abstract] [Full Text]  
• Pavio, N., Romano, P. R., Graczyk, T. M., Feinstone, S. M., Taylor, D. R. (2003). Protein Synthesis and Endoplasmic Reticulum Stress Can Be Modulated by the Hepatitis C Virus Envelope Protein E2 through the Eukaryotic Initiation Factor 2{alpha} Kinase PERK. J. Virol. 77: 3578-3585 [Abstract] [Full Text]