
<ArticleTitle>Toxicity of human adenovirus <prot>E4orf4</prot> protein in Saccharomyces cerevisiae results from interactions with the <prot>Cdc55</prot> regulatory B subunit of <prot>PP2A</prot>.</ArticleTitle>
<AbstractText>The <prot>E4orf4</prot> protein of human adenovirus induces <prot>p53</prot>-independent apoptosis, a process that may promote cell death and viral spread. When expressed alone, <prot>E4orf4</prot> kills transformed cells but not normal human cells. The only clear target of <prot>E4orf4</prot> in mammalian cells is the Balpha (B55) subunit of <prot>protein phosphatase 2A</prot> (<prot>PP2A</prot>), a member of one of three classes of regulatory B subunits. Here we report the effects of <prot>E4orf4</prot> in Saccharomyces cerevisiae, which encodes two <prot>PP2A</prot> regulatory B subunits, <prot>CDC55</prot> and <prot>RTS1</prot>, that share homology with mammalian B and B' subunits, respectively. <prot>E4orf4</prot> expression was found to be toxic in yeast, resulting in the accumulation of cells in G2/M phase that failed to grow upon removal of <prot>E4orf4</prot>. <prot>E4orf4</prot>-expressing yeast also displayed an elongated cell morphology similar to <prot>cdc55</prot> deletion strains. <prot>E4orf4</prot> required <prot>CDC55</prot> to elicit its effect, whereas <prot>RTS1</prot> was dispensable. The recruitment of the <prot>PP2A</prot> holoenzyme by <prot>E4orf4</prot> was entirely dependent on <prot>Cdc55</prot>. These studies indicate that <prot>E4orf4</prot>-induced apoptosis in mammalian cells and cell death in yeast require functional interactions with B-type subunits of <prot>PP2A</prot>. However, some inhibition of growth by <prot>E4orf4</prot> was observed in the <prot>cdc55</prot> strain and with an <prot>E4orf4</prot> mutant that fails to interact with <prot>Cdc55</prot>, indicating that <prot>E4orf4</prot> may possess a second <prot>Cdc55</prot>-independent function affecting cell growth.</AbstractText>
