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Targeting of adenovirus E1A and E4-ORF3 proteins to nuclear matrix-associated PML bodies
T Carvalho1, J S Seeler, K Ohman
1Instituto de Histologia, Faculdade de Medicina, Lisboa, Portugal.
Abstract:
The PML protein was first identified as part of a fusion product with the retinoic acid receptor alpha (RAR alpha), resulting from the t(15;17) chromosomal translocation associated with acute promyelocytic leukemia (APL). It has been previously demonstrated that PML, which is tightly bound to the nuclear matrix, concentrates in discrete subnuclear compartments that are disorganized in APL cells due to the expression of the PML-RAR alpha hybrid. Here we report that adenovirus infection causes a drastic redistribution of PML from spherical nuclear bodies into fibrous structures. The product encoded by adenovirus E4-ORF3 is shown to be responsible for this reorganization and to colocalize with PML into these fibers. In addition, we demonstrate that E1A oncoproteins concentrate in the PML domains, both in infected and transiently transfected cells, and that this association requires the conserved amino acid motif (D)LXCXE, common to all viral oncoproteins that bind pRB or the related p107 and p130 proteins. The SV-40 large T antigen, another member of this oncoprotein family is also found in close association with the PML nuclear bodies. Taken together, the present data indicate that the subnuclear domains containing PML represent a preferential target for DNA tumor viruses, and therefore suggest a more general involvement of the PML nuclear bodies in oncogenic processes.
Insights
Adenovirus infection reorganizes promyelocytic leukemia (PML) protein nuclear bodies into fibrous structures. This suggests PML nuclear bodies are a target for DNA tumor viruses, implicating them in oncogenesis.
Area of Science:
- Cell Biology
- Virology
- Oncology
Background:
- Promyelocytic leukemia (PML) protein forms nuclear bodies, crucial in cellular processes.
- PML nuclear bodies are disrupted in acute promyelocytic leukemia (APL) by the PML-RAR alpha fusion protein.
- PML protein's role in oncogenesis is suggested by its association with APL.
Purpose of the Study:
- To investigate the effect of adenovirus infection on PML nuclear bodies.
- To identify the viral component responsible for PML redistribution.
- To explore the interaction between viral oncoproteins and PML nuclear bodies.
Main Methods:
- Adenovirus infection of cells.
- Cellular and molecular biology techniques to study protein localization and interaction.
- Analysis of protein colocalization using microscopy.
Main Results:
- Adenovirus infection drastically redistributes PML protein from nuclear bodies to fibrous structures.
- Adenovirus E4-ORF3 protein is responsible for this PML reorganization and colocalizes with PML.
- Viral oncoproteins, including E1A and SV-40 large T antigen, associate with PML nuclear bodies.
Conclusions:
- PML nuclear bodies are a preferential target for DNA tumor viruses.
- The interaction between viral oncoproteins and PML nuclear bodies suggests a broader role for PML in oncogenic processes.
- Adenovirus E4-ORF3 mediates the disruption of PML nuclear bodies, highlighting viral manipulation of host cell structures.