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Journal of Virology, November 2008, p. 10477-10486, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01113-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Encodes Three Bona Fide Ubiquitin-Specific Proteases{triangledown} ,{ddagger}

Ramakrishna Sompallae,1,{dagger} Stefano Gastaldello,1,2,{dagger} Sebastian Hildebrand,1 Nikolay Zinin,1 Gerco Hassink,1 Kristina Lindsten,1 Juergen Haas,3 Bengt Persson,1,4 and Maria G. Masucci1*

Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden,1 Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy,2 Division of Pathway Medicine, School of Biomedical Sciences, College of Medicine, University of Edinburgh, Edinburgh, United Kingdom, and Max von Pettenkofer-Institute, LMU-München, Munich, Germany,3 IFM Bioinformatics, Linköping University, S-581 83 Linköping, Sweden4

Received 27 May 2008/ Accepted 8 August 2008

Manipulation of the ubiquitin proteasome system (UPS) is emerging as a common theme in viral pathogenesis. Some viruses have been shown to encode functional homologs of UPS enzymes, suggesting that a systematic identification of these products may provide new insights into virus-host cell interactions. Ubiquitin-specific proteases, collectively known as deubiquitinating enzymes (DUBs), regulate the activity of the UPS by hydrolyzing ubiquitin peptide or isopeptide bonds. The prediction of viral DUBs based on sequence similarity with known enzymes is hampered by the diversity of viral genomes. In this study sequence alignments, pattern searches, and hidden Markov models were developed for the conserved C- and H-boxes of the known DUB families and used to search the open reading frames (ORFs) of Epstein-Barr virus (EBV), a large gammaherpesvirus that has been implicated in the pathogenesis of a broad spectrum of human malignancies of lymphoid and epithelial cell origin. The searches identified a limited number of EBV ORFs that contain putative DUB catalytic domains. DUB activity was confirmed by functional assays and mutation analysis for three high scoring candidates, supporting the usefulness of this bioinformatics approach in predicting distant homologues of cellular enzymes.

* Corresponding author. Mailing address: Karolinska Institutet, Box 285, 171 77, Stockholm, Sweden. Phone: 46 8 52486755. Fax: 46 8 337412. E-mail: maria.masucci{at}ki.se

{triangledown} Published ahead of print on 20 August 2008.

{ddagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{dagger} R.S. and S.G. contributed equally to this study.

Journal of Virology, November 2008, p. 10477-10486, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.01113-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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