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 Qiang, W. Articles by Wong, P. K. Y. Search for Related Content PubMed PubMed Citation Articles by Qiang, W. Articles by Wong, P. K. Y.

 Previous Article  |  Next Article 

Journal of Virology, November 2004, p. 11926-11938, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11926-11938.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activation of Transcription Factor Nrf-2 and Its Downstream Targets in Response to Moloney Murine Leukemia Virus ts1-Induced Thiol Depletion and Oxidative Stress in Astrocytes

Wenan Qiang , Jodi M. Cahill, Jinrong Liu , Xianghong Kuang, Na Liu, Virginia L. Scofield, Jennifer R. Voorhees, Amy J. Reid, Mingshan Yan, William S. Lynn, and Paul K. Y. Wong^*

University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas

Received 7 April 2004/ Accepted 21 June 2004

The neuroimmunodegenerative syndrome that develops in mice infected with ts1, a mutant of Moloney murine leukemia virus, resembles human AIDS. Both ts1 and human immunodeficiency virus type 1 infect astrocytes, microglia, and oligodendrocytes but do not infect neurons. Oxidative stress has been implicated in the neuropathology of AIDS dementia and other neurodegenerative diseases. We report here that ts1 infection of astrocytes (both transformed C1 cells and primary cultures) also induces thiol (i.e., glutathione and cysteine) depletion and reactive oxygen species (ROS) accumulation, events occurring in parallel with viral envelope precursor gPr80^env accumulation and upregulated expression of endoplasmic reticulum chaperones GRP78 and GRP94. Furthermore, ts1-infected astrocytes mobilize their thiol redox defenses by upregulating levels of the Nrf-2 transcription factor, as well its targets, the xCT cystine/glutamate antiporter, -glutamylcysteine ligase, and glutathione peroxidase. Depleting intracellular thiols by treating uninfected astrocytes with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, or by culturing in cystine-deficient medium, also induces ROS accumulation, activates Nrf-2, and upregulates Nrf-2 target gene expression in these astrocytes. Overexpression of Nrf-2 in astrocytes specifically increases expression of the above thiol synthesis-related proteins. Further treatment with BSO or N-acetylcysteine in transfected cells modulates this expression. Thiol depletion also accelerates cell death, while thiol supplementation promotes survival of ts1-infected cells. Together, our results indicate that ts1 infection of astrocytes, along with ts1-induced gPr80^env accumulation, endoplasmic reticulum stress, thiol depletion, and oxidative stress, accelerates cell death; in response to the thiol depletion and oxidative stress, astrocytes activate their Nrf-2-mediated thiol antioxidant defenses, promoting cell survival.

---

* Corresponding author. Mailing address: University of Texas, M. D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, TX 78957. Phone: (512) 237-9456. Fax: (512) 237-2444. E-mail: pkwong{at}mdanderson.org.

Present address: Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

Present address: Drug Metabolism Department, Abbott Laboratories, Abbott Park, IL 60064.

Present address: Department of Nutrition, University of Texas at Austin, Austin, TX 78712.

---

Journal of Virology, November 2004, p. 11926-11938, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11926-11938.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Portis, J. L., Askovich, P., Austin, J., Gutierrez-Cotto, Y., McAtee, F. J. (2009). The Degree of Folding Instability of the Envelope Protein of a Neurovirulent Murine Retrovirus Correlates with the Severity of the Neurological Disease. J. Virol. 83: 6079-6086 [Abstract] [Full Text]  
• Sorci, G., Faivre, B. (2009). Inflammation and oxidative stress in vertebrate host-parasite systems. Phil Trans R Soc B 364: 71-83 [Abstract] [Full Text]  
• Antony, J. M., Ellestad, K. K., Hammond, R., Imaizumi, K., Mallet, F., Warren, K. G., Power, C. (2007). The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes. J. Immunol. 179: 1210-1224 [Abstract] [Full Text]  
• Clase, A. C., Dimcheff, D. E., Favara, C., Dorward, D., McAtee, F. J., Parrie, L. E., Ron, D., Portis, J. L. (2006). Oligodendrocytes Are a Major Target of the Toxicity of Spongiogenic Murine Retroviruses. Am. J. Pathol. 169: 1026-1038 [Abstract] [Full Text]  
• Jiang, Y., Scofield, V. L., Yan, M., Qiang, W., Liu, N., Reid, A. J., Lynn, W. S., Wong, P. K. Y. (2006). Retrovirus-Induced Oxidative Stress with Neuroimmunodegeneration Is Suppressed by Antioxidant Treatment with a Refined Monosodium {alpha}-Luminol (Galavit). J. Virol. 80: 4557-4569 [Abstract] [Full Text]  
• Qiang, W., Kuang, X., Liu, J., Liu, N., Scofield, V. L., Reid, A. J., Jiang, Y., Stoica, G., Lynn, W. S., Wong, P. K. Y. (2006). Astrocytes Survive Chronic Infection and Cytopathic Effects of the ts1 Mutant of the Retrovirus Moloney Murine Leukemia Virus by Upregulation of Antioxidant Defenses.. J. Virol. 80: 3273-3284 [Abstract] [Full Text]  
• Kaleeba, J. A. R., Berger, E. A. (2006). Kaposi's sarcoma-associated herpesvirus fusion-entry receptor: cystine transporter xCT.. Science 311: 1921-1924 [Abstract] [Full Text]