Modulation intrinsischer Immunität durch adenovirale Onkoproteine

点击翻译按钮获取中文摘要

The adenovirus (Ad) oncoproteins E1B-55K and E4orf6 are multifunctional regulators of Ad replication participating in many processes required for maximal virus production and Ad-mediated oncogenesis. Their growth-promoting activities correlate with their ability to interact with and to manipulate a number of key regulators of cell growth. Prominent examples are tumor suppressors (e.g. p53), DNA repair proteins, components of the ubiquitin- and SUMO-conjugation machineries, and other cellular restriction factors, which may confer an intrinsic immunity against Ad infections. Recent work from our group indicates that these factors are different components of PML nuclear bodies (PML-NBs), whose antiviral activity is manipulated likely through posttranslational mechanisms (e.g. SUMOylation).In the proposed project we plan to further investigate these host factors and to uncover the role of PML-NBs in the antiviral and cellular growth control at the molecular level. Work will be focused on genetic and biochemical analyses of the PML-NB-associated tumor suppressor protein PML and its six isoforms as well on studies of the viral interaction partners (E1B-55K and E4orf6) in lytically infected and transformed cells. In the context of these studies we will also address the question, whether E1B-55K antagonizes the antiviral properties of the PML-NBs through an intrinsic E3 SUMO ligase activity. Finally the function(s) of the specific PML isoforms as mediators of an intrinsic antiviral and/or anti-oncogenic barrier will be clarified through the analyses of isoform-specific reconstituted cell lines.Overall, this project aims for an understanding of the molecular mechanism by which pathogenic human viruses usurp the host cell machinery for efficient progeny production and cell transformation. These studies should reveal novel strategies of viral replication and pathogenesis, as well as virus-mediated cell transformation, and thus provide a platform for the design of anti-viral as well as anti-cancer therapeutics. It appears that the analysis of the Ad oncoproteins E1B-55K and E4orf6 is particularly suitable as a model system because their lytic and oncogenic properties underlie fundamental principles of viral replication and virus-induced cell transformation.