Impact of herpesvirus protein kinases on host protein modification
疱疹病毒蛋白激酶对宿主蛋白修饰的影响
基本信息
- 批准号:8888392
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-05-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:BindingBioinformaticsBiologyCellsCellular biologyComplexCytomegalovirusDNA DamageEnsureEnvironmentEnzymesEventFosteringFutureHTATIP geneHerpesviridaeHerpesvirus 1HumanHuman Herpesvirus 4Human Herpesvirus 8In VitroInfectionInfectious MononucleosisKnowledgeLeadLife Cycle StagesMalignant NeoplasmsMass Spectrum AnalysisMediatingMentorsModificationNuclearPathway interactionsPhasePhosphorylationPhosphorylation SitePhosphotransferasesPost-Translational Protein ProcessingProtein KinaseProtein MicrochipsProteinsProteomicsRoleScientistSignal TransductionSiteTrainingUbiquitinValidationViralViral ProteinsVirus ReplicationWorkbasecellular targetingdrug developmentexperiencehigh throughput screeningin vivoinsightlytic replicationmembermultidisciplinarynovelnovel strategiespathogenresponsesuccessvirology
项目摘要
The Epstein-Barr virus (EBV) protein kinase BGLF4 is a member of the conserved herpesvirus protein
kinases, a group of enzymes conserved throughout all subfamilies of Herpesviridae. Knowledge of the cellular
protein substrates of BGLF4 is essential for understanding BGLF4 function; however, only a small number of
host substrates have been characterized to date. In addition to inducing protein phosphorylation, BGLF4 also
regulates global host protein SUMOylation in a kinase activity dependent manner; however, no specific
examples of a BGLF4 regulated host protein have been described. To understand the changes brought about in
the cellular environment by EBV infeciton, it is not only critical to identify the BGLF4 in vivo targets and their
precise phosphorylation sites, but also to have an approach that can unambiguously dissect the complex
signaling networks regulated by BGLF4. We previously identified several hundred host substrates
phosphorylated in vitro by EBV BGLF4 and by three other orthologous kinases. Bioinformatic analysis of their
shared substrates revealed that proteins involved in the DNA damage response (DDR) pathway were
statistically enriched. Further studies demonstrated that BGLF4 actively induces a host DDR via TIP60
phosphorylation to foster viral replication. Interestingly, my recent work demonstrated that binding of the small
ubiquitin-like modifier (SUMO) is critical for the BGLF4-induced protein phosphorylation involved in the DDR.
BGLF4 also inhibits host protein SUMOylation in both a SUMO binding and kinase activity dependent manner.
Based on these observations, I hypothesize that EBV BGLF4 induces a dynamic alteration of cellular
protein phosphorylation and SUMOylation to create a suitable environment for efficient virus replication.
In order to precisely identify the signaling events downstream of BGLF4, I will work with my co-mentor Dr.
Akhilesh Pandey, who is a leading scientist in mass spectrometry, proteomics and bioinformatics. My primary
mentor Dr. Diane Hayward, who has over 30 years experience with EBV, will guide my validation of the host
substrates and demonstration of their role in EBV biology. Specifically, during the K99 phase, I will globally
identify BGLF4-regulated phosphorylation and SUMOylation targets in EBV-infected cells, pinpoint the key host
pathways targeted by BGLF4, and validate the identified substrates. In the R00 phase, I will elucidate the
mechanisms by which BGLF4 mediated changes in phosphorylation and SUMOylation of host proteins facilitate
virus replication. My proposed studies during the mentored phase of this application are an ideal vehicle for
multidisciplinary training in virology, proteomics and bioinformatics, all of which will ensure my future success in
the subsequent independent phase. The proposed studies are novel in that they explore the role of a viral
protein BGLF4 as an active player in regulating the crosstalk between protein phosphorylation and
SUMOylation. They will also significantly increase our understanding of viral manipulation of host
phosphoryation and SUMOylation, which should lead to novel insights into pathogen-host interactions.
eb病毒(EBV)蛋白激酶BGLF4是保守疱疹病毒蛋白的一个成员
项目成果
期刊论文数量(0)
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{{ truncateString('Renfeng Li', 18)}}的其他基金
Impact of herpesvirus protein kinases on host protein modification
疱疹病毒蛋白激酶对宿主蛋白修饰的影响
- 批准号:
8488143 - 财政年份:2013
- 资助金额:
$ 24.9万 - 项目类别:
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