Epstein-barr virus encodes three bona fide ubiquitin-specific proteases.
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.
Sompallae
Ramakrishna
R
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. maria.masucci@ki.se
Gastaldello
Stefano
S
Hildebrand
Sebastian
S
Zinin
Nikolay
N
Hassink
Gerco
G
Lindsten
Kristina
K
Haas
Juergen
J
Persson
Bengt
B
Masucci
Maria G
MG
D020816:Amino Acid Motifs; D019943:Amino Acid Substitution / Q000235:genetics; D019677:Artificial Gene Fusion; D019295:Computational Biology; D017124:Conserved Sequence; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000201:enzymology* / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D064570:Ubiquitin-Specific Proteases; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; D010450:Endopeptidases; D064570:Ubiquitin-Specific Proteases