Adenovirus type 5 E4orf3 protein relieves p53 inhibition by E1B-55-kilodalton protein.
The E1B-55-kDa protein of adenovirus type 5 and the p53 tumor suppressor gene product form a complex that localizes to the cytoplasm, thereby downregulating p53's transcriptional activity. The E4orf6 protein binds and relocalizes E1B-55-kDa, and the proteins act synergistically to inactivate p53. We show that another adenovirus E4 gene product, E4orf3, is also sufficient to relocalize E1B-55-kDa from the cytoplasm to the nucleus. Both proteins are then found in discrete nuclear structures (tracks) that are known to contain components of the promyelocytic leukemia-associated nuclear structure. Simultaneously, p53 is dissociated from E1B-55-kDa and is found evenly distributed over the nucleoplasm. In the presence of E4orf3, p53-dependent transcriptional activity is no longer repressed by E1B-55-kDa. When E1B-55-kDa is coexpressed with E4orf3 and E4orf6, E1B-55-kDa is found to colocalize with E4orf6 rather than E4orf3. In parallel, p53 is inhibited and degraded by the combination of E1B-55-kDa and E4orf6, regardless of coexpressed E4orf3. This suggests that the effects of E4orf6 on E1B-55-kDa overrule the actions of E4orf3. When cells are infected with virus expressing E4orf3 but not E4orf6, E1B is found in the cell nucleus and p53 enters the virus replication centers. After infection with wild-type adenovirus, E4orf3 is expressed before E4orf6 and E1B temporarily colocalizes with E4orf3 in nuclear tracks before associating with E4orf6. We propose that during adenovirus infection, the E4orf3 protein transiently liberates p53 from its association with E1B-55-kDa. Subsequently, p53 is inactivated and degraded by the combination of E1B-55-kDa and E4orf6.
König
C
C
Institut für Virologie, Zentrum für Mikrobiologie und Hygiene, Philipps-Universität Marburg, 35037 Marburg, Germany.
Roth
J
J
Dobbelstein
M
M
D017501:Adenovirus E1B Proteins / Q000502:physiology*; D017504:Adenovirus E4 Proteins / Q000502:physiology*; D002467:Cell Nucleus / Q000737:chemistry; D002478:Cells, Cultured; D004261:DNA Replication; D008970:Molecular Weight; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000037:antagonists & inhibitors*; D014779:Virus Replication