Mechanisms of histone crosstalk with bacterial pathogens
组蛋白与细菌病原体串扰的机制
基本信息
- 批准号:10574141
- 负责人:
- 金额:$ 28.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-11-18 至 2024-10-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino AcidsAnkyrin RepeatArchitectureBindingBinding ProteinsBiochemicalBypassCatalysisCell NucleusCell physiologyCell secretionCellsChromatinCodeComplexComplex MixturesCryoelectron MicroscopyCytoplasmDNADepositionDetectionEnvironmentEnzyme InteractionEnzymesEpigenetic ProcessEukaryotaFoundationsFreezingFutureGene ExpressionGenesGenetic TranscriptionGenomeGoalsHistone CodeHistone H3Histone-Lysine N-MethyltransferaseHistonesHumanImmuneImmune EvasionImmune Response GenesIndividualInfectionLegionella pneumophilaLegionnaires&apos DiseaseLysineMethylationMethyltransferaseModelingModificationMutateNorleucineNucleosomesPathogenicityPatternPeptidesPhysiologyPreparationProcessProliferatingProteinsRegulationSET DomainSamplingSignal PathwayStructureTestingTranscriptional RegulationWorkchromatin modificationdensityepigenomeexperimental studygene repressionhistone methylationhistone modificationhuman pathogenimprovedinhibitorinsightmetaplastic cell transformationmicrobialnon-Nativepathogenpathogenic bacteriapreferenceprogramsscreening
项目摘要
PROJECT SUMMARY
Bacterial pathogens modulate the physiology of human cells by secreting effector proteins that assist pathogen
immune evasion and proliferation. The diverse repertoire of secreted pathogenic effectors re-wire an array of
cellular signaling pathways that are at the core of host cell function. One class of these effector proteins enter
the human cell nucleus and directly modulate transcriptional programs of the host by altering our epigenetic
code. These so-called epigenetic “nucleomodulins” represent an important aspect of host-pathogen interaction,
however very little is understood about how these effectors might interact with and sense the epigenetic
landscape of the host cell during infection. One of the most well-studied epigenetic nucleomodulins is RomA, a
histone lysine methyltransferase from Legionella pneumophila, the causative agent of Legionnaires Disease.
RomA mono-, di- and tri-methylates histone H3K14, silences the expression of host cell immune response
genes and enables efficient replication of L. pneumophila inside the host cytoplasm. RomA contains several
domains that are conserved in eukaryotic chromatin-binding proteins, suggesting that its H3K14 methylation
activity may be regulated by interacting with histone modifications of the host. In eukaryotes, the phenomenon
where an existing histone modification controls the recognition or deposition of another is called histone
modification crosstalk. These histone crosstalk mechanisms underlie the complex regulation of transcription
and genome architecture in eukaryotes. However, there are no known examples of a bacterial pathogen that
can interpret human histone modifications through histone crosstalk and alter the human epigenome. Such an
observation would greatly expand our understanding of host-pathogen interactions during infection. In this R21
proposal, we will use the L. pneumophila effector RomA as a model to establish if pathogenic bacteria can
interact with and interpret existing histone modifications through crosstalk mechanisms. In Aim 1, we will
subject RomA and individual RomA domains to a comprehensive three-part screen to establish if any human
histone modifications can bind to RomA or regulate its catalytic activity. Then, in Aim 2 we will establish a cryo-
EM screening workflow to identify optimal substrates and freezing conditions that will be necessary to
determine a structure of RomA bound to its preferred substrate nucleosome.
项目摘要
细菌病原体通过分泌效应蛋白来调节人体细胞的生理学,
免疫逃避和增殖。分泌的致病效应物的多样性重新连接了一系列的
细胞信号通路是宿主细胞功能的核心。其中一类效应蛋白进入
人类细胞核,并通过改变我们的表观遗传直接调节宿主的转录程序
代码.这些所谓的表观遗传“核调节蛋白”代表了宿主-病原体相互作用的一个重要方面,
然而,很少有人了解这些效应器如何与表观遗传相互作用,
在感染过程中宿主细胞的景观。研究最充分的表观遗传核调节蛋白之一是RomA,
来自嗜肺军团菌的组蛋白赖氨酸甲基转移酶,是军团菌病的病原体。
RomA单、二和三甲基化组蛋白H3 K14,沉默宿主细胞免疫应答的表达
基因,并使L.嗜肺菌在宿主细胞质内。Roma包含多个
真核细胞染色质结合蛋白中保守的结构域,表明其H3 K14甲基化
活性可以通过与宿主的组蛋白修饰相互作用来调节。在真核生物中,
其中一个现有的组蛋白修饰控制另一个组蛋白的识别或沉积,
修正串扰这些组蛋白串扰机制是复杂的转录调控的基础
和真核生物的基因组结构。然而,没有已知的细菌病原体的例子,
可以通过组蛋白串扰解释人类组蛋白修饰并改变人类表观基因组。这样的
观察将大大扩展我们对感染期间宿主-病原体相互作用的理解。在R21中
建议,我们将使用L。嗜肺菌效应子RomA作为模型,以确定致病菌是否可以
通过串扰机制与现有组蛋白修饰相互作用并解释现有组蛋白修饰。在目标1中,我们
对RomA和单个RomA域进行全面的三部分筛选,以确定是否存在人类
组蛋白修饰可以与RomA结合或调节其催化活性。第二,我们将建立一个冷的,
EM筛选工作流程,以确定必要的最佳底物和冷冻条件,
确定与其优选底物核小体结合的RomA的结构。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Evan J Worden其他文献
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{{ truncateString('Evan J Worden', 18)}}的其他基金
Epigenetic Mechanisms of Retrotransposon Silencing
逆转录转座子沉默的表观遗传机制
- 批准号:
10701916 - 财政年份:2022
- 资助金额:
$ 28.5万 - 项目类别:
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