NKLAM: An RBR E3 Ubiquitin Ligase Essential for Regulation of Innate Immunity
NKLAM:一种 RBR E3 泛素连接酶,对于调节先天免疫至关重要
基本信息
- 批准号:9898218
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2021-09-30
- 项目状态:已结题
- 来源:
- 关键词:Activated Natural Killer CellAddressAffectAgingAnti-Bacterial AgentsAntibiotic ResistanceApoptosisApoptoticAutoimmune DiseasesBCL2 geneBacteriaBacterial Antibiotic ResistanceBiologicalCarcinogensCell DeathCell SurvivalCell physiologyCellsCellular StructuresCommunicable DiseasesDataDefectDiseaseDrug ModulationEffector CellEventExhibitsExposure toFrequenciesGenesGoalsGrowthHealthcare SystemsImmune responseImmune systemImmunityIn VitroInfectionInfectious AgentInflammatoryIngestionInnate Immune SystemKnockout MiceLaboratoriesLigaseLightLyticMalignant - descriptorMalignant NeoplasmsMediatingMediator of activation proteinMedicalMembraneMilitary PersonnelMolecularMultiple MyelomaMusNatural ImmunityNatural Killer CellsNatureNeoplasm MetastasisPathogenesisPathway interactionsPlayPopulationProteinsRegulationRestRiskRoleSTAT1 geneSignal TransductionSiteStaphylococcus aureusStreptococcus pneumoniaeSubstrate InteractionSystemTestingTherapeuticTherapeutic InterventionTranscriptional RegulationUbiquitinationUridine KinaseVeteransWild Type Mouseantimicrobialassaultc-myc Genescancer cellcell growthclinically significantcomorbiditycytokinedrug discoveryexosomefirst responderin vivointerestmacrophagemembermicrovesiclesmouse modelneoplastic cellnervous system disordernovel therapeutic interventionpathogenpreventprogramsresponsetranscription factortumortumor growthubiquitin-protein ligase
项目摘要
The innate immune system serves is the first response to diseased cells and infectious agents. Natural
Killer (NK) cells and macrophages are primary components of this system. Although their functions differ, they
both require the expression of NKLAM (Natural Killer Lytic-Associated Molecule) for optimal function.
Accordingly, elucidating the role of NKLAM in innate immunity has important biological and clinical significance.
NKLAM is up-regulated in NK cells upon exposure to tumor cells or cytokines that activate cytolytic
function. NKLAM is up-regulated in macrophages upon exposure to bacteria or pro-inflammatory cytokines. We
generated NKLAM-deficient (KO) mice; they have less NK activity than WT (wild type) mice. They exhibit greater
tumor growth, tumor dissemination and metastasis than WT mice. NKLAM KO mice also have defects in
macrophage anti-bacterial function in vivo and in vitro.
NKLAM is a member of a small, highly conserved, unique group of RING-in between-RING (RBR) E3
ubiquitin ligases. RBR E3 ubiquitin ligases play a key role in cellular physiology and are involved in the
pathogenesis of many diseases, including cancer, autoimmune diseases and neurological disorders. There is
great interest in drug discovery to target them. We identified key potential substrates of NKLAM-mediated
ubiquitination, including the transcription factors STAT1 and c-myc, Bcl-2 and UCKL-1 (uridine cytidine kinase
like-1), a protein that promotes tumor growth. The central nature of these substrates in cell signaling, growth and
survival suggests that drug modulation of NKLAM has significant potential for treating cancer and infectious
diseases.
We found that activated NK cells releases exosomes containing NKLAM. NKLAM+ exosomes promote
tumor cell death in vitro. Preliminary data indicate that NKLAM+ exosomes enter target cells and deliver NKLAM.
Important unanswered questions that will be addressed are the effect of NKLAM on critical substrates in effector
cells and in target cells.
The role of NKLAM in macrophages is undoubtedly different from its role in NK cells in that killing of
bacteria occurs intracellularly. Our ongoing studies suggest that NKLAM modulates the signaling events that
activate the macrophage anti-bacterial program. A key regulator of this pathway is STAT1.
We will test the hypothesis that the E3 ubiquitin ligase activity of NKLAM plays a role in the anti-tumor
and anti-microbial functions of NK cells and macrophages with the following three interconnected but
independent aims:
Aim 1: Elucidate the role of NKLAM in exosome-mediated killing of tumor cells. We will test the
hypothesis that upon entry of NK-derived exosomes containing NKLAM into tumor cells, NKLAM interacts with
critical substrates, resulting in cell death. We will test the ability of exosomes from NKLAM WT, NKLAM KO and
NKLAM ligase defective NK cells to kill tumor cells in vivo using a mouse model of multiple myeloma, a disease
increasing in frequency, especially in veterans.
Aim 2: Determine how NKLAM affects the anti-bacterial function of macrophages in vitro and in vivo. We
will infect NKLAM KO and WT mice with S. pneumoniae and S. aureus, pathogens that are leading causes of
disease. In light of increasing antibiotic resistance, the importance of these in vivo studies is magnified.
Aim 3: Identify the mechanism, sites and types of ubiquitination mediated by NKLAM. We will examine
substrates important in tumor growth and anti-bacterial killing. This will provide a better understanding of the role
of NKLAM in anti-tumor and anti-bacterial immunity and reveal key regulatory steps susceptible to therapeutic
interventions for diseases that afflict our veteran population.
先天免疫系统是对病态细胞和感染性病原体的第一反应。天然
杀伤(NK)细胞和巨噬细胞是这个系统的主要组成部分。虽然它们的功能不同,但它们
两者都需要NKLAM(自然杀伤溶解相关分子)的表达才能发挥最佳功能。
因此,阐明NKLAM在先天免疫中的作用具有重要的生物学意义和临床意义。
NKLAM在NK细胞暴露于肿瘤细胞或激活细胞溶解的细胞因子时上调
功能。NKLAM在暴露于细菌或促炎细胞因子的巨噬细胞中上调。我们
产生NKLAM缺陷(KO)小鼠;它们的NK活性低于WT(野生型)小鼠。他们表现出更大的
肿瘤生长、肿瘤扩散和转移能力均优于WT小鼠。NKLAM KO小鼠也有缺陷
体内和体外巨噬细胞的抗菌功能。
NKLAM是一个小的、高度保守的、独特的环内环间(RBR)E3组的成员
泛素连接酶。RBR E3泛素连接酶在细胞生理学中发挥关键作用,并参与
许多疾病的发病机制,包括癌症、自身免疫性疾病和神经疾病。的确有
对药物发现非常感兴趣,以此为目标。我们确定了NKLAM介导的关键潜在底物
泛素化,包括转录因子STAT1和c-myc、Bcl2和UKL-1(尿苷胞苷激酶
Like-1),一种促进肿瘤生长的蛋白质。这些底物的中心性质在细胞信号、生长和
存活表明NKLAM的药物调节在治疗癌症和感染性疾病方面具有巨大的潜力
疾病。
我们发现,激活的NK细胞释放含有NKLAM的外切体。NKLAM+外切体促进
肿瘤细胞在体外死亡。初步数据表明,NKLAM+外切体进入靶细胞并运送NKLAM。
将解决的重要悬而未决的问题是NKLAM对效应器中关键底物的影响
细胞和目标细胞中。
NKLAM在巨噬细胞中作用与其在NK细胞中杀伤巨噬细胞的作用无疑是不同的
细菌存在于细胞内。我们正在进行的研究表明,NKLAM调节信号事件,
激活巨噬细胞抗菌程序。该途径的一个关键调节因子是STAT1。
我们将验证NKLAM的E3泛素连接酶活性在抗肿瘤中发挥作用的假设
NK细胞和巨噬细胞的抗微生物功能与以下三个相互关联但
独立目标:
目的1:阐明NKLAM在外切体介导的肿瘤细胞杀伤中的作用。我们将测试
假设当含有NKLAM的NK来源的外切体进入肿瘤细胞时,NKLAM与
关键底物,导致细胞死亡。我们将测试NKLAM WT,NKLAM KO和NKLAM KO的外体的能力
NKLAM连接缺陷NK细胞在多发性骨髓瘤小鼠模型中体内杀伤肿瘤细胞
频率增加的,尤其是退伍军人。
目的2:研究NKLAM在体内外对巨噬细胞抗菌功能的影响。我们
将用肺炎链球菌和金黄色葡萄球菌感染NKLAM KO和WT小鼠,这两种病原体是导致
疾病。鉴于抗生素耐药性的增加,这些体内研究的重要性被放大。
目的3:确定NKLAM介导的泛素化的机制、部位和类型。我们将研究
在肿瘤生长和抗细菌杀灭中很重要的底物。这将提供对角色的更好理解
NKLAM在抗肿瘤和抗细菌免疫中的作用并揭示对治疗敏感的关键调控步骤
对折磨我们退伍军人人口的疾病进行干预。
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Extracellular Vesicles From the Human Natural Killer Cell Line NK3.3 Have Broad and Potent Anti-Tumor Activity.
来自人类天然杀手细胞系NK3.3的细胞外囊泡具有广泛而有效的抗肿瘤活性。
- DOI:10.3389/fcell.2021.698639
- 发表时间:2021
- 期刊:
- 影响因子:5.5
- 作者:Cochran AM;Kornbluth J
- 通讯作者:Kornbluth J
E3 ubiquitin ligase NKLAM positively regulates macrophage inducible nitric oxide synthase expression.
- DOI:10.1016/j.imbio.2014.08.016
- 发表时间:2015-01
- 期刊:
- 影响因子:2.8
- 作者:Lawrence, Donald W.;Gullickson, Gail;Kornbluth, Jacki
- 通讯作者:Kornbluth, Jacki
E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity.
- DOI:10.1016/j.cellsig.2016.08.014
- 发表时间:2016-12
- 期刊:
- 影响因子:4.8
- 作者:Lawrence DW;Kornbluth J
- 通讯作者:Kornbluth J
Natural Killer Lytic-Associated Molecule (NKLAM): An E3 Ubiquitin Ligase With an Integral Role in Innate Immunity.
- DOI:10.3389/fphys.2020.573372
- 发表时间:2020
- 期刊:
- 影响因子:4
- 作者:Lawrence DW;Willard PA;Cochran AM;Matchett EC;Kornbluth J
- 通讯作者:Kornbluth J
NK3.3-Derived Extracellular Vesicles Penetrate and Selectively Kill Treatment-Resistant Tumor Cells.
- DOI:10.3390/cancers16010090
- 发表时间:2023-12-23
- 期刊:
- 影响因子:5.2
- 作者:Mccune, Allyson;Kornbluth, Jacki;Wong, David
- 通讯作者:Wong, David
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JACKI KORNBLUTH其他文献
JACKI KORNBLUTH的其他文献
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{{ truncateString('JACKI KORNBLUTH', 18)}}的其他基金
Molecular Characterization of Anti-Tumor Activity Mediated by Extracellular Vesicles Derived from Natural Killer Cells
自然杀伤细胞来源的细胞外囊泡介导的抗肿瘤活性的分子表征
- 批准号:
10587355 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Development of Natural Killer (NK) Cell Line-Derived Extracellular Vesicles as a New Treatment for Cancer
开发自然杀伤 (NK) 细胞系衍生的细胞外囊泡作为癌症的新治疗方法
- 批准号:
10383462 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
- 批准号:
8413781 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
- 批准号:
8696768 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
- 批准号:
8795661 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
- 批准号:
8243104 - 财政年份:2012
- 资助金额:
-- - 项目类别:
PLATELET-ACTIVATING FACTOR AND METASTASIS: CALCIUM-INDEPENDENT PHOSPHOLIPASE
血小板激活因子和转移:钙非依赖性磷脂酶
- 批准号:
8361461 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Role of Natural Killer Lytic-Associated Molecule (NKLAM) in Natural Killer Functi
自然杀伤裂解相关分子 (NKLAM) 在自然杀伤功能中的作用
- 批准号:
8123617 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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