Interaction of MEQ protein and C-terminal-binding protein is critical for induction of lymphomas by Marek's disease virus.
Marek's disease virus (MDV) is an oncogenic herpesvirus that induces fatal T cell lymphomas in chickens. With more than 20 billion doses of vaccine used annually, vaccination constitutes the cornerstone of Marek's disease control. Despite the success of vaccination, evolution of virulence among MDV strains continues to threaten the effectiveness of the current Marek's disease vaccines. MDV-encoded protein MEQ (MDV EcoRI Q) probably acts as a transcription factor and is considered to be the major MDV oncoprotein. MEQ sequence shows a Pro-Leu-Asp-Leu-Ser (PLDLS) motif known to bind C-terminal-binding protein (CtBP), a highly conserved cellular transcriptional corepressor with roles in the regulation of development, proliferation, and apoptosis. Here we show that MEQ can physically and functionally interact with CtBP through this motif and that this interaction is critical for oncogenesis because mutations in the CtBP-interaction domain completely abolished oncogenicity. This direct role for MEQ-CtBP interaction in MDV oncogenicity highlights the convergent evolution of molecular mechanisms of neoplastic transformation by herpesviruses because Epstein-Barr virus oncoproteins EBNA 3A and 3C also interact with CtBP. We also demonstrate that the nononcogenic MDV generated by mutagenesis of the CtBP-interaction domain of MEQ has the potential to be an improved vaccine against virulent MDV infection. Engineering MDV with precisely defined attenuating mutations, therefore, represents an effective strategy for generating new vaccines against this major poultry disease.
Brown
Andrew C
AC
Viral Oncogenesis Group, Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, United Kingdom.
Baigent
Susan J
SJ
Smith
Lorraine P
LP
Chattoo
Jason P
JP
Petherbridge
Lawrence J
LJ
Hawes
Pippa
P
Allday
Martin J
MJ
Nair
Venugopal
V
D000429:Alcohol Oxidoreductases; D000595:Amino Acid Sequence; D000818:Animals; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002642:Chick Embryo; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D025922:Mardivirus / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D016415:Sequence Alignment; D015996:Survival Rate
D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein