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.