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 Lefèbvre, L.
Right arrow Articles by Willems, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lefèbvre, L.
Right arrow Articles by Willems, L.

 Previous Article  |  Next Article 

Journal of Virology, February 2002, p. 1400-1414, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1400-1414.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Oncoviral Bovine Leukemia Virus G4 and Human T-Cell Leukemia Virus Type 1 p13II Accessory Proteins Interact with Farnesyl Pyrophosphate Synthetase

Laurent Lefèbvre,1 Alain Vanderplasschen,2 Vincenzo Ciminale,3 Hubertine Heremans,4 Olivier Dangoisse,1 Jean-Claude Jauniaux,5 Jean-François Toussaint,6 Vlado Zelnik,7 Arsène Burny,1 Richard Kettmann,1 and Luc Willems1*

Faculty of Agronomy, Gembloux,1 Faculty of Veterinary Medicine, University of Liège, Liège,2 Rega Institute, University of Leuven, Leuven,4 Veterinary and Agrochemical Research Centre, Uccle, Belgium,6 Department of Oncology and Surgical Sciences, University of Padova, Padua, Italy,3 DKFZ, Heidelberg, Germany,5 Institute of Virology, Bratislava, Slovak Republic7

Received 20 July 2001/ Accepted 19 October 2001

G4 and p13II are accessory proteins encoded by the X region of bovine leukemia virus and human T-cell leukemia virus type 1 (HTLV-1), respectively. Disruption of the G4 and p13II open reading frames interferes with viral spread in animal model systems, indicating that the corresponding proteins play a key role in viral replication. In addition, G4 is oncogenic in primary cell cultures and is absolutely required for efficient onset of leukemogenesis in sheep. To gain insight into the function of these proteins, we utilized the yeast two-hybrid system to identify protein partners of G4. Results revealed that G4 interacts with farnesyl pyrophosphate synthetase (FPPS), a protein involved in the mevalonate/squalene pathway and in synthesis of FPP, a substrate required for prenylation of Ras. The specificity of the interaction was verified by glutathione S-transferase (GST) pull-down assays and by coimmunoprecipitation experiments. Furthermore, confocal microscopy showed that the subcellular localization of G4 was profoundly affected by FPPS. The G4 protein itself was not prenylated, at least in rabbit reticulocyte lysate-based assays. The domain of G4 required for binding to FPPS was restricted to an amphipathic {alpha}-helix rich in arginine residues. Subtle mutation of this {alpha}-helix abrogated G4 oncogenic potential in vitro, providing a biological relevance for FPPS-G4 complex formation in cells. Finally, HTLV-1 p13II was also found to specifically interact with FPPS (in yeast as well as in GST pull-down assays) and to colocalize with G4 in mitochondria, suggesting a functional analogy between these oncoviral accessory proteins. Identification of FPPS as a molecular partner for p13II and G4 accessory proteins opens new prospects for treatment of retrovirus-induced leukemia.

* Corresponding author. Mailing address: Molecular and Cellular Biology, Faculté Universitaire des Sciences Agronomiques (FUSAG), 13 ave. Maréchal Juin, B5030 Gembloux, Belgium. Phone: 32-81-622157. Fax: 32-81-613888. E-mail: willems.l{at}fsagx.ac.be.

Journal of Virology, February 2002, p. 1400-1414, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1400-1414.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Florins, A., Gillet, N., Boxus, M., Kerkhofs, P., Kettmann, R., Willems, L. (2007). Even Attenuated Bovine Leukemia Virus Proviruses Can Be Pathogenic in Sheep. J. Virol. 81: 10195-10200 [Abstract] [Full Text]  
  • Waldele, K., Silbermann, K., Schneider, G., Ruckes, T., Cullen, B. R., Grassmann, R. (2006). Requirement of the human T-cell leukemia virus (HTLV-1) tax-stimulated HIAP-1 gene for the survival of transformed lymphocytes. Blood 107: 4491-4499 [Abstract] [Full Text]  
  • Hiraragi, H., Michael, B., Nair, A., Silic-Benussi, M., Ciminale, V., Lairmore, M. (2005). Human T-Lymphotropic Virus Type 1 Mitochondrion-Localizing Protein p13II Sensitizes Jurkat T Cells to Ras-Mediated Apoptosis. J. Virol. 79: 9449-9457 [Abstract] [Full Text]  
  • Waldele, K., Schneider, G., Ruckes, T., Grassmann, R. (2004). Interleukin-13 Overexpression by Tax Transactivation: a Potential Autocrine Stimulus in Human T-Cell Leukemia Virus-Infected Lymphocytes. J. Virol. 78: 6081-6090 [Abstract] [Full Text]  
  • Silic-Benussi, M., Cavallari, I., Zorzan, T., Rossi, E., Hiraragi, H., Rosato, A., Horie, K., Saggioro, D., Lairmore, M. D., Willems, L., Chieco-Bianchi, L., D'Agostino, D. M., Ciminale, V. (2004). Suppression of tumor growth and cell proliferation by p13II, a mitochondrial protein of human T cell leukemia virus type 1. Proc. Natl. Acad. Sci. USA 101: 6629-6634 [Abstract] [Full Text]  
  • D'Agostino, D. M., Ranzato, L., Arrigoni, G., Cavallari, I., Belleudi, F., Torrisi, M. R., Silic-Benussi, M., Ferro, T., Petronilli, V., Marin, O., Chieco-Bianchi, L., Bernardi, P., Ciminale, V. (2002). Mitochondrial Alterations Induced by the p13II Protein of Human T-cell Leukemia Virus Type 1. CRITICAL ROLE OF ARGININE RESIDUES. J. Biol. Chem. 277: 34424-34433 [Abstract] [Full Text]  
  • Albrecht, B., Lairmore, M. D. (2002). Critical Role of Human T-Lymphotropic Virus Type 1 Accessory Proteins in Viral Replication and Pathogenesis. Microbiol. Mol. Biol. Rev. 66: 396-406 [Abstract] [Full Text]  
  • Lefebvre, L., Ciminale, V., Vanderplasschen, A., D'Agostino, D., Burny, A., Willems, L., Kettmann, R. (2002). Subcellular Localization of the Bovine Leukemia Virus R3 and G4 Accessory Proteins. J. Virol. 76: 7843-7854 [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»