title: E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor.
abstract: Adenovirus inundates the productively infected cell with linear, double-stranded DNA and an abundance of single-stranded DNA. The cellular response to this stimulus is antagonized by the adenoviral E1B and E4 early genes. A mutant group C adenovirus that fails to express the E1B-55K and E4orf3 genes is unable to suppress the DNA-damage response. Cells infected with this double-mutant virus display significant morphological heterogeneity at late times of infection and frequently contain fragmented nuclei. Nuclear fragmentation was due to the translocation of apoptosis inducing factor (AIF) from the mitochondria into the nucleus. The release of AIF was dependent on active poly(ADP-ribose) polymerase-1 (PARP-1), which appeared to be activated by viral DNA replication. Nuclear fragmentation did not occur in AIF-deficient cells or in cells treated with a PARP-1 inhibitor. The E1B-55K or E4orf3 proteins independently prevented nuclear fragmentation subsequent to PARP-1 activation, possibly by altering the intracellular distribution of PAR-modified proteins.
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Roberta L
authors.initials: RL
authors.lastname: Turner
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: john.wilkinson@ndsu.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Wilkinson
authors.affiliation: Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States. Electronic address: ornelles@wakehealth.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Ornelles
mesh_terms: D017501:Adenovirus E1B Proteins / Q000378:metabolism*; D017504:Adenovirus E4 Proteins / Q000378:metabolism*; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014779:Virus Replication
chemical_list: D017501:Adenovirus E1B Proteins; D017504:Adenovirus E4 Proteins; D051033:Apoptosis Inducing Factor; D004279:DNA, Viral; D015513:Oncogene Proteins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: Adenovirus; Apoptosis inducing factor; E1B-55K; E4orf3; Nuclear morphology; Poly (ADP-ribose) polymerase-1