The adenovirus E4 open reading frame 4 (E4orf4) protein is a multifunctional viral regulator that contributes to temporal regulation of the progression of viral infection. When expressed outside the context of the virus, E4orf4 induces p53-independent cell death in transformed cells. Oncogenic transformation of primary cells in tissue culture sensitizes them to cell killing by E4orf4,1 indicating that E4orf4 research may have implications for cancer therapy. It has been further reported that E4orf4 induces a caspase-independent, non-classical apoptotic pathway that maintains crosstalk with classical caspase-dependent pathways.2,3 An investigation into the mechanisms involved in E4orf4-induced cell death revealed that E4orf4 interacts with the heterotrimeric protein phosphatase 2A (PP2A) through direct association with its regulatory B subunits, and the interaction mediated by the PP2A Bα/B55 subunit is required for inducing cell death.1 Furthermore, E4orf4 recruits PP2A to a new substrate, the ACF chromatin remodeling factor, which contributes to E4orf4 functions.4 E4orf4 has also been reported to associate with members of the Src kinase family, leading to its Tyr phosphorylation and to deregulation of Src signaling, resulting in enhanced cell death.2 We showed previously that the interaction between E4orf4 and PP2A and its toxic consequences were conserved from yeast to mammals,5 indicating a high degree of evolutionary conservation of the underlying mechanisms. This finding suggested the feasibility of using various model organisms for studying E4orf4-induced cell death. Indeed, our work in yeast revealed a novel E4orf4 partner, Ynd1, a Golgi UDPase that contributes to E4orf4 toxicity.6