Structure and Function of Legionella pneumophila Lysine Methyltransferases
嗜肺军团菌赖氨酸甲基转移酶的结构和功能
基本信息
- 批准号:10595019
- 负责人:
- 金额:$ 54.23万
- 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:2022-03-21 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgreementAmericanAmino AcidsAmoeba genusAnkyrin RepeatArchitectureBacterial PneumoniaBindingBiochemicalBiochemistryBiocideBiologicalBiological AssayBiological ProcessC-terminalCategoriesCell DeathCell NucleusCellsChromatinChronic lung diseaseComplementComplexCoupledCryoelectron MicroscopyDNADataDefectDiseaseDistalElderlyElementsEnzymesEtiologyExhibitsFatality rateFoundationsGene DeletionGene ExpressionGene Expression RegulationGenesHistone H3Histone-Lysine N-MethyltransferaseHistonesImmuneImmune responseImmunocompromised HostImpairmentIn VitroIndividualInfectionInnate Immune ResponseKineticsLaboratoriesLegionellaLegionella pneumophilaLegionnaires&apos DiseaseLungLysineMacrophageMapsMediatingMembraneMethylationMethyltransferaseMichiganMicrobiologyModificationMolecularMorbidity - disease rateMutagenesisMutationN-terminalNatural ImmunityNuclearNucleosomesOrthologous GeneParis, FrancePathogenesisPathogenicityPeptidesProtein SecretionProteinsReaderRepressionRoentgen RaysRoleS-AdenosylhomocysteineS-AdenosylmethionineSET DomainSignal PathwaySignal TransductionSiteSpecificityStructureSubstrate SpecificityTailTestingUniversitiesVirulenceatypical pneumoniachromatin modificationcombatgene repressiongenome-widehistone methylationinhibitorinsightinterdisciplinary collaborationmicroscopic imagingmolecular pathologymortalitymutantnanomolarnovelnovel therapeuticsparticlepathogenpathogenic bacteriaprogramsstructural biologytherapeutic developmenttrafficking
项目摘要
PROJECT ABSTRACT
Legionella pneumophila is a intracellular bacterial pathogen that is the primary etiological agent of Legionnaires’
Disease. This disease is categorized as an atypical pneumonia that afflicts the elderly and individuals who are
immunocompromised or suffer from chronic lung disease. L. pneumophila infects host cells, such as
environmental amoeba and lung macrophages, through the secretion of an array of effector proteins that subvert
signaling pathways, membrane trafficking, and gene expression in host cells to promote bacterial replication.
Among these effectors are the protein lysine methyltransferases (KMTs) RomA and its highly conserved strain
ortholog LegAS4. RomA has been shown to localize to the nucleus where it trimethylates Lys14 in histone H3
(H3K14me3). This novel chromatin modification silences the macrophage gene expression, including loci
responsible for innate immunity. In agreement with these findings, deletion of the RomA gene in L. pneumophila
hinders bacterial replication within infected host cells, illustrating the importance of this KMT in pathogenesis.
Despite the role of RomA in L. pneumophila virulence, outstanding questions regarding the biological functions
of RomA and LegAS4 remain unresolved. These questions include the molecular basis of their unique substrate
specificity for H3K14, how they interact with chromatin, and the biological roles of LegAS4 in host cell infection.
The Trievel, Swanson, Cho, and Ohi laboratories at the University of Michigan have established an
interdisciplinary collaboration to address these questions by employing an integrated approach combining
biochemistry, microbiology, and structural biology. Our overall objective is to elucidate the mechanism by which
RomA and LegAS4 recognize and methylate H3K14 in nucleosomes in vitro and in host cells infected by L.
pneumophila. We propose the following specific aims to accomplish this objective:
1) Define the molecular mechanism of H3K14 methylation by RomA and LegAS4.
2) Elucidate the structural basis of nucleosome recognition.
3) Determine the functions of LegAS4 in macrophage infection.
We envision that these studies will yield a comprehensive framework for understanding the mechanisms
underlying nucleosome recognition and H3K14 methylation by RomA and LegAS4 that promote L. pneumophila
replication during host cell infection. These results will provide avenues for developing selective inhibitors of
these KMTs that can be applied as novel therapeutics or biocides to combat Legionnaires Disease.
项目摘要
嗜肺军团菌是一种细胞内细菌病原体,是军团菌病的主要病原体。
疾病。这种疾病被归类为非典型肺炎,影响老年人和以下个人
免疫功能受损或患有慢性肺部疾病。嗜肺性乳杆菌感染宿主细胞,例如
环境阿米巴和肺巨噬细胞,通过分泌一系列颠覆
宿主细胞中促进细菌复制的信号通路、膜运输和基因表达。
在这些效应物中有蛋白赖氨酸甲基转移酶(KMTs)、RomA及其高度保守的菌株
正交系4。已经证明,RomA定位于细胞核,在那里它对组蛋白H3中的Lys14进行三甲基化
(H3K14me3)。这种新的染色质修饰沉默了巨噬细胞的基因表达,包括基因座
负责先天免疫力。与这些发现一致的是,嗜肺乳杆菌中rom基因的缺失
阻止细菌在受感染的宿主细胞内复制,说明这种KMT在发病机制中的重要性。
尽管RomA在嗜肺乳杆菌毒力中发挥了作用,但关于其生物学功能的悬而未决的问题
罗马和Legas 4的问题仍然悬而未决。这些问题包括它们独特底物的分子基础。
H3K14的特异性,它们如何与染色质相互作用,以及LegAS4在宿主细胞感染中的生物学作用。
密歇根大学的Trievel,Swanson,Cho和Ohi实验室已经建立了一个
跨学科协作,通过采用综合方法来解决这些问题
生物化学、微生物学和结构生物学。我们的总体目标是阐明
RomA和LegAS4在体外核小体和感染L.
嗜肺症。为实现这一目标,我们提出了以下具体目标:
1)明确了罗马基因和LegAS4基因甲基化H3K14的分子机制。
2)阐明核小体识别的结构基础。
3)确定LegAS4在巨噬细胞感染中的作用。
我们设想,这些研究将为理解这些机制提供一个全面的框架。
RomA和LegAS4促进嗜肺乳杆菌核小体识别和H3K14甲基化的基础
在宿主细胞感染期间进行复制。这些结果将为开发选择性抑制剂提供途径。
这些KMT可作为新型疗法或杀生剂应用于防治退伍军人病。
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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RAYMOND C TRIEVEL其他文献
RAYMOND C TRIEVEL的其他文献
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{{ truncateString('RAYMOND C TRIEVEL', 18)}}的其他基金
Structure and Function of Legionella pneumophila Lysine Methyltransferases
嗜肺军团菌赖氨酸甲基转移酶的结构和功能
- 批准号:
10445910 - 财政年份:2022
- 资助金额:
$ 54.23万 - 项目类别:
Homocitrate Synthase Inhibitors as Novel Antifungal Agents for Aspergillus
高柠檬酸合酶抑制剂作为曲霉菌的新型抗真菌剂
- 批准号:
8683888 - 财政年份:2014
- 资助金额:
$ 54.23万 - 项目类别:
Homocitrate Synthase Inhibitors as Novel Antifungal Agents for Aspergillus
高柠檬酸合酶抑制剂作为曲霉菌的新型抗真菌剂
- 批准号:
8916542 - 财政年份:2014
- 资助金额:
$ 54.23万 - 项目类别:
Structure and Function of SET Domain Methyltransferases
SET结构域甲基转移酶的结构和功能
- 批准号:
7933154 - 财政年份:2009
- 资助金额:
$ 54.23万 - 项目类别:
Structure and Function of SET Domain Methyltransferases
SET结构域甲基转移酶的结构和功能
- 批准号:
7033457 - 财政年份:2006
- 资助金额:
$ 54.23万 - 项目类别:
Structure and Function of SET Domain Methyltransferases
SET结构域甲基转移酶的结构和功能
- 批准号:
7765581 - 财政年份:2006
- 资助金额:
$ 54.23万 - 项目类别:
Structure and Function of SET Domain Methyltransferases
SET结构域甲基转移酶的结构和功能
- 批准号:
7350235 - 财政年份:2006
- 资助金额:
$ 54.23万 - 项目类别:
Structure and Function of SET Domain Methyltransferases
SET结构域甲基转移酶的结构和功能
- 批准号:
7167747 - 财政年份:2006
- 资助金额:
$ 54.23万 - 项目类别:
Structure and Function of SET Domain Methyltransferases
SET结构域甲基转移酶的结构和功能
- 批准号:
7571638 - 财政年份:2006
- 资助金额:
$ 54.23万 - 项目类别:
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