Modulation intrinsischer Immunität durch adenovirale Onkoproteine

腺病毒癌蛋白对内在免疫的调节

• 批准号: 234760463
• 负责人: Professor Dr. Thomas Dobner
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234760463?language=en
• 关键词: Modulation; intrinsischer; Immunit; durch; adenovirale

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.

腺病毒（AD）癌蛋白E1B-55K和E4ORF6是AD复制的多功能调节剂，参与了许多最大病毒生产和AD介导的肿瘤发生所需的许多过程。他们的促进生长活动与它们与细胞生长的许多关键调节剂相互作用和操纵的能力相关。突出的例子是肿瘤抑制剂（例如p53），DNA修复蛋白，泛素 - 偶联机器的成分以及其他细胞限制因子，这可能会赋予针对AD感染的内在隐身。我们小组的最新工作表明，这些因素是PML核体（PML-NBS）的不同组成部分，其抗病毒活性可能是通过翻译后机制（例如Sumoylation）操纵的。在拟议的项目中，我们计划进一步研究这些宿主因素并发现PML-NBS在抗生激发和细胞生长中的作用。工作将集中在PML-NB相关的肿瘤抑制蛋白PML及其六种同工型的遗传和生化分析上，以及对病毒相互作用伙伴（E1B-55K和E4ORF6）的研究，在溶血感染和转化的细胞中。在这些研究的背景下，我们还将解决一个问题，E1B-55K是否通过固有的E3 Sumo连接酶活性拮抗PML-NB的抗病毒作用。最后，特定PML同工型的功能将通过分析来阐明同工型特异性重构细胞系的介导子，将阐明该项目旨在通过哪种病原体人体病毒病毒的宿主进行宿主的生产和有效地转化分子机制，以了解分子机制。这些研究应揭示病毒复制和发病机理的新型策略，以及病毒介导的细胞转化，从而为抗病毒和抗癌治疗的设计提供了一个平台。看来对AD癌蛋白E1B-55K和E4ORF6的分析特别适合作为模型系统，因为它们的裂解和致癌特性是病毒复制和病毒诱导的细胞转化的基本原理的基础。

项目成果

Cross-talk between phosphorylation and SUMOylation regulates transforming activities of an adenoviral oncoprotein

• DOI: 10.1038/onc.2012.187
• 发表时间: 2013-03-28
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Wimmer, P.;Blanchette, P.;Dobner, T.
• 通讯作者: Dobner, T.

Humanized Mice Reproduce Acute and Persistent Human Adenovirus Infection

人源化小鼠再现急性和持续性人类腺病毒感染

• DOI: 10.1093/infdis/jiw499
• 发表时间: 2017
• 期刊: The Journal of Infectious Diseases
• 作者: Rodriguez;Hartmann;Pilnitz-Stolze;Gomez-Medina;Munoz-Fontela;Krasemann;Dobner
• 通讯作者: Dobner

PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53

• DOI: 10.1038/onc.2015.63
• 发表时间: 2016-01
• 期刊: Oncogene
• 影响因子: 8
• 作者: P. Wimmer;J. Berscheminski;P. Blanchette;P. Groitl;P. Branton;Ronald T. Hay;T. Dobner;S. Schreiner

Efficient Transformation of Primary Human Mesenchymal Stromal Cells by Adenovirus Early Region 1 Oncogenes

• DOI: 10.1128/jvi.01782-16
• 发表时间: 2017-01-01
• 期刊: JOURNAL OF VIROLOGY
• 影响因子: 5.4
• 作者: Speiseder, Thomas;Hofmann-Sieber, Helga;Dobner, Thomas
• 通讯作者: Dobner, Thomas

Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation

• DOI: 10.1038/onc.2015.378
• 发表时间: 2016-06-16
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Berscheminski, J.;Brun, J.;Schreiner, S.
• 通讯作者: Schreiner, S.