Role of Ifitm/Fragilis proteins as intracellular shuttles during cell activation
Ifitm/Fragilis 蛋白在细胞激活过程中作为细胞内穿梭机的作用
基本信息
- 批准号:8197848
- 负责人:
- 金额:$ 18.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-12-01 至 2013-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAnimalsAutoimmunityB-LymphocytesBindingBiologicalBiological AssayCD81 geneCell ProliferationCell Surface ReceptorsCell membraneCell physiologyCell surfaceCellsCellular MembraneComplexCytoplasmDepressed moodDown-RegulationEnzymesEventFamily memberFutureGoalsHumanImmuneImmune responseInfectionInterferon ActivationInterferon Type IIInterferonsLeadLocationMammalian CellMembraneMembrane MicrodomainsMembrane ProteinsModelingModificationMolecularMovementMusNormal CellPathway interactionsPhagocytesPhenocopyPhenotypePost-Translational Protein ProcessingProductionPropertyProtein BindingProtein KinaseProteinsPublicationsRestRoleSet proteinSignal TransductionSiteSurfaceTestingTissuesUbiquitinViralVirusVirus DiseasesYeastsbasedesignhuman PHEMX proteinmacrophagemanmigrationpreventprotein degradationprotein functionpublic health relevancereceptorresearch studyresponserestorationyeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant): The central focus of this project is to test the hypothesis that the Ifitm proteins down-modulate cell activation and prevent viral infections by shuttling modifying enzymes to the cell surface to degrade activation complexes. The activation of cells of the immune response often requires signaling through cell surface receptors. This event brings into activation domains, such as lipid rafts, both the activating proteins (kinases, etc) and the substrates (receptors and intracellular signaling partners). In some cells (phagocytic cells such as macrophages and B cells) many such complexes are internalized and degraded. Other activation complexes on these and other cells, however, remain on the cell surface and require modification to block further cellular activation. The Ifitm proteins have been characterized as functioning to help down-regulate activated cells, depressing adhesion and proliferation. In addition they were recently characterized as the major determinants of the anti-viral state in mammalian cells after activation with type I and type II interferons. However, the mechanism by which the Ifitm proteins accomplish these effects has not been described. We have found that the Ifitm proteins can bind to a variety of proteins whose functions are associated with the modification of proteins by the addition of substrates (such as ubiquitin or SUMO) or enzymatic cleavage. We propose that the Ifitm proteins are held within the cell and are released following activation to intercalate within the membrane. As the Ifitm proteins make this migration, they carry these modifying proteins as cargo for association with proteins within the membrane. The delivery of these cargo proteins into activation complexes is followed by their action to degrade and/or modify surface proteins thus depressing cell activation. This same pathway is also proposed to function to control viral infection. We propose to target one specific cargo protein in particular, Bat5, which has been shown to bind to the Ifitm proteins of man and mouse. We further propose that the absence of this pathway will allow for uninhibited cellular activation potentially leading to increased cell proliferation and lack of immune control that could lead to autoimmunity and tissue damage.
PUBLIC HEALTH RELEVANCE: The control of cell activation requires pathways that down regulate activating complexes and components. The Ifitm proteins have been implicated as helping depress cell activation and enhance innate immune defenses to certain viral infections but no mechanisms as to how they accomplish this have been demonstrated. We propose to test the hypothesis that the Ifitm proteins shuttle cargo enzymes into membrane activation complexes. These enzymes then target constituents of such sites for modification and degradation thus depressing activation and inhibiting infection.
描述(由申请方提供):本项目的中心重点是检验Ifitm蛋白下调细胞活化并通过将修饰酶穿梭至细胞表面以降解活化复合物来预防病毒感染的假设。 免疫应答的细胞的激活通常需要通过细胞表面受体的信号传导。该事件将激活蛋白(激酶等)和底物(受体和细胞内信号传导伴侣)带入激活结构域,如脂筏。在某些细胞(吞噬细胞如巨噬细胞和B细胞)中,许多这样的复合物被内化和降解。然而,这些和其他细胞上的其他活化复合物保留在细胞表面上,需要修饰以阻断进一步的细胞活化。Ifitm蛋白已被表征为起作用以帮助下调活化的细胞,抑制粘附和增殖。此外,它们最近被表征为在用I型和II型干扰素活化后哺乳动物细胞中抗病毒状态的主要决定因素。然而,Ifitm蛋白实现这些作用的机制尚未描述。 我们已经发现,Ifitm蛋白可以结合多种蛋白,其功能与通过添加底物(如泛素或SUMO)或酶促裂解修饰蛋白有关。我们提出Ifitm蛋白被保持在细胞内,并在激活后释放以嵌入膜内。当Ifitm蛋白进行这种迁移时,它们携带这些修饰蛋白作为与膜内蛋白质缔合的货物。将这些货物蛋白递送到活化复合物中之后是它们降解和/或修饰表面蛋白的作用,从而抑制细胞活化。同样的途径也被认为可以控制病毒感染。我们建议靶向一种特定的货物蛋白,特别是Bat 5,它已被证明与人和小鼠的Ifitm蛋白结合。我们进一步提出,缺乏这种途径将允许不受抑制的细胞活化,可能导致细胞增殖增加和缺乏免疫控制,这可能导致自身免疫和组织损伤。
公共卫生相关性:细胞活化的控制需要下调活化复合物和组分的途径。Ifitm蛋白被认为有助于抑制细胞活化并增强对某些病毒感染的先天免疫防御,但尚未证明它们如何实现这一点的机制。我们建议测试的假设,Ifitm蛋白穿梭货物酶到膜活化复合物。然后这些酶靶向这些位点的成分进行修饰和降解,从而抑制活化和抑制感染。
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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John Weis其他文献
John Weis的其他文献
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{{ truncateString('John Weis', 18)}}的其他基金
Role of Ifitm/Fragilis proteins as intracellular shuttles during cell activation
Ifitm/Fragilis 蛋白在细胞激活过程中作为细胞内穿梭机的作用
- 批准号:
8043909 - 财政年份:2010
- 资助金额:
$ 18.69万 - 项目类别:
Regulation of CR2/CD21 Expression and Activation
CR2/CD21 表达和激活的调节
- 批准号:
7880369 - 财政年份:2009
- 资助金额:
$ 18.69万 - 项目类别:
Role of the Fragilis Proteins in the Immune Response
脆弱蛋白在免疫反应中的作用
- 批准号:
6894009 - 财政年份:2004
- 资助金额:
$ 18.69万 - 项目类别:
Role of the Fragilis Proteins in the Immune Response
脆弱蛋白在免疫反应中的作用
- 批准号:
6804271 - 财政年份:2004
- 资助金额:
$ 18.69万 - 项目类别:
Role of Pactolus in the innate immune response
Pactolus 在先天免疫反应中的作用
- 批准号:
6631980 - 财政年份:1998
- 资助金额:
$ 18.69万 - 项目类别:
PACTOLUS AND MAST CELL AND MORROW CELL FUNCTION
PACTOLUS、肥大细胞和莫罗细胞功能
- 批准号:
2705528 - 财政年份:1998
- 资助金额:
$ 18.69万 - 项目类别:
Role of Pactolus in the innate immune response
Pactolus 在先天免疫反应中的作用
- 批准号:
6886799 - 财政年份:1998
- 资助金额:
$ 18.69万 - 项目类别:
Role of Pactolus in the innate immune response
Pactolus 在先天免疫反应中的作用
- 批准号:
6721189 - 财政年份:1998
- 资助金额:
$ 18.69万 - 项目类别:
PACTOLUS AND MAST CELL AND MORROW CELL FUNCTION
PACTOLUS、肥大细胞和莫罗细胞功能
- 批准号:
2887616 - 财政年份:1998
- 资助金额:
$ 18.69万 - 项目类别:
PACTOLUS AND MAST CELL AND MORROW CELL FUNCTION
PACTOLUS、肥大细胞和莫罗细胞功能
- 批准号:
6170928 - 财政年份:1998
- 资助金额:
$ 18.69万 - 项目类别:
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