Mitochondrial localization of p53 during adenovirus infection and regulation of its activity by E1B-19K.
Recent results have revealed that the p53 tumor suppressor protein possesses a direct transcription-independent apoptotic activity. During apoptosis induced by genotoxic stress, a small fraction of p53 is targeted to mitochondria where it initiates apoptosis by causing mitochondrial dysfunction. In adenovirus-infected cells, the expression of E1A protein enhances the accumulation of p53 during early phases of infection and during late times after infection, it is targeted for degradation by the combined action of E1B-55K and E4-orf6 proteins. The functional significance of E1A-mediated accumulation of p53 during early phases of viral replication is not known. Our studies with isogenic epithelial cell lines that differ only on the status of p53 indicate that Ad infection induces apoptosis by p53-dependent and -independent pathways and both pathways are suppressed by E1B-19K. We show that during early phase of Ad infection, a fraction of p53 is targeted to the mitochondria. In virus infected cells, a large fraction of the viral antiapoptosis protein E1B-19K is also localized in mitochondria during early and late phases of infection. Coimmunoprecipitation analysis has revealed that p53 and E1B-19K form a complex in mitochondria. The interaction of 19K involves two noncontiguous regions located around amino-acid residues 14-15 and 123-124. On p53, the mutations within the DNA-binding domain reduce interaction with E1B-19K. Our studies also suggest that 19K may additionally complex with the multidomain mitochondrial proapoptotic protein BAK, thereby reducing the level of p53 interaction with BAK. We suggest that p53-induced apoptosis may be important for efficient cell lysis and viral spread and that E1B-19K may neutralize the apoptotic activity of p53 at multiple levels.
Lomonosova
Elena
E
Institute for Molecular Virology, Saint Louis University School of Medicine, 3681 Park Avenue, St Louis, MO 63110, USA.
Subramanian
T
T
Chinnadurai
G
G
D000256:Adenoviridae / Q000302:isolation & purification / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000502:physiology*; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D021381:Protein Transport; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
D017501:Adenovirus E1B Proteins; C494772:BAK1 protein, human; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein