title: E4orf4 induces PP2A- and Src-dependent cell death in Drosophila melanogaster and at the same time inhibits classic apoptosis pathways.
abstract: The adenovirus E4orf4 protein regulates the progression of viral infection, and when expressed alone in mammalian tissue culture cells it induces protein phosphatase 2A (PP2A)-B55- and Src-dependent cell death, which is more efficient in oncogene-transformed cells than in normal cells. This form of cell death is caspase-independent, although it interacts with classic caspase-dependent apoptosis. PP2A-B55-dependent E4orf4-induced toxicity is highly conserved in evolution from yeast to mammalian cells. In this work we investigated E4orf4-induced cell death in a whole multicellular organism, Drosophila melanogaster. We show that E4orf4 induced low levels of cell killing, caused by both caspase-dependent and -independent mechanisms. Drosophila PP2A-B55 (twins/abnormal anaphase resolution) and Src64B contributed additively to this form of cell death. Our results provide insight into E4orf4-induced cell death, demonstrating that in parallel to activating caspase-dependent apoptosis, E4orf4 also inhibited this form of cell death induced by the proapoptotic genes reaper, head involution defective, and grim. The combination of both induction and inhibition of caspase-dependent cell death resulted in low levels of tissue damage that may explain the inefficient cell killing induced by E4orf4 in normal cells in tissue culture. Furthermore, E4orf4 inhibited JNK-dependent cell killing as well. However, JNK inhibition did not impede E4orf4-induced toxicity and even enhanced it, indicating that E4orf4-induced cell killing is a distinctive form of cell death that differs from both JNK- and Rpr/Hid/Grim-induced forms of cell death.
authors.affiliation: Department of Molecular Microbiology and Genetics, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Antonina
authors.initials: A
authors.lastname: Pechkovsky
authors.forename: Maoz
authors.initials: M
authors.lastname: Lahav
authors.forename: Eliya
authors.initials: E
authors.lastname: Bitman
authors.forename: Adi
authors.initials: A
authors.lastname: Salzberg
authors.forename: Tamar
authors.initials: T
authors.lastname: Kleinberger
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D008957:Models, Genetic; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D017956:Photoreceptor Cells, Invertebrate / Q000502:physiology; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014921:Wings, Animal / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C121517:E4orf4 protein, adenovirus; D014764:Viral Proteins; D019061:src-Family Kinases; D010749:Phosphoprotein Phosphatases; C079898:tws protein, Drosophila; D020169:Caspases