Dissecting the contribution of SREBPs and lipid biosynthesis to inflammasome function
剖析 SREBP 和脂质生物合成对炎症小体功能的贡献
基本信息
- 批准号:8981979
- 负责人:
- 金额:$ 3.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-11-01 至 2017-10-31
- 项目状态:已结题
- 来源:
- 关键词:25-hydroxycholesterolAdaptor Signaling ProteinAgonistAmericanAtherosclerosisBacteriaBinding ProteinsBiochemicalBone MarrowCaspase-1CellsCholesterolClustered Regularly Interspaced Short Palindromic RepeatsConfocal MicroscopyDataDiseaseEnvironmentEnzyme InductionEnzymesFamilyFamily memberGene TargetingGenesGenetic TranscriptionImmune responseImmunosuppressive AgentsInfectionInflammationInflammation MediatorsInflammatoryInterferon Type IInterferonsInterleukin-1Intracellular MembranesLinkLipidsLipopolysaccharidesMass Spectrum AnalysisMediatingMembraneMessenger RNAMetabolicMetabolic syndromeMixed Function OxygenasesMolecular ChaperonesMorbidity - disease rateMusMyeloid CellsNuclearPathway interactionsPeptide HydrolasesPhenotypePlayProcessProductionProteinsRecruitment ActivityRegulationRepressionResponse ElementsRoleSterolsSystemTestingToll-like receptorsbasecholesterol biosynthesischolesterol-binding proteincytokineextracellularfatty acid biosynthesisimmunopathologylipid biosynthesismacrophagepathogenpreventprotein activationprotein complexpublic health relevancereceptorreconstitutionresearch studyresponsesensortherapy developmenttranscription factor
项目摘要
DESCRIPTION (provided by applicant): Interleukin-1 family members are key inflammatory cytokines in the innate immune response to infection. While IL-1 is necessary for proper defense against pathogens, the production of this cytokine must be carefully regulated in order to prevent immunopathology. One checkpoint on the release of IL-1 family cytokines is their requirement for post-translational processing by a multi-protein complex known as the inflammasome, which serves as a platform for recruiting and activating the protease caspase-1. Sensing of extracellular bacteria by Toll-like receptors (TLRs) triggers the transcription of il1b mRNA, but IL-1ß is not released until inflammasome sensor proteins recognize bacterial products that have entered the cellular cytosolic compartment. Type I interferons (IFN-I) are known to inhibit inflammasome activity, which partially explains their long-recognized immunosuppressive capacity, although the underlying mechanisms have been unclear. Induction of the enzyme Ch25h, which produces 25-hydroxycholesterol (25-HC) from cholesterol, is a key component of IFN-I- mediated inhibition of inflammasomes. Ch25h is an IFN-I-stimulated gene in macrophages, and deletion of Ch25h results in increased capase-1 activity and release of IL-1ß. 25-HC is a potent suppressor of the Sterol Response Element Binding Protein (SREBP) cholesterol biosynthetic pathway, and Ch25h-deficient macrophages additionally display increased SREBP pathway activity after TLR stimulation. Deletion of SCAP, a protein required for SREBP activation, in macrophages results in decreased inflammasome activity. Based on these data, I aim to characterize how the SREBP pathway positively regulates inflammasomes. Specifically, I propose to determine the necessity and sufficiency of SREBP proteins in augmenting inflammasome function, and to define which step of inflammasome activation they regulate (Aim 1). I also propose to test the hypothesis that SREBPs promote inflammasome function via the production of cholesterol (Aim 2).
描述(由申请人提供):白细胞介素-1家族成员是对感染的先天免疫应答中的关键炎性细胞因子。虽然IL-1对于适当防御病原体是必需的,但必须仔细调节这种细胞因子的产生以防止免疫病理学。IL-1家族细胞因子释放的一个检查点是它们需要通过称为炎性体的多蛋白复合物进行翻译后加工,所述炎性体用作募集和激活蛋白酶胱天蛋白酶-1的平台。Toll样受体(TLR)对细胞外细菌的感知触发了IL-1b mRNA的转录,但是IL-1b直到炎性体传感器蛋白识别已经进入细胞胞质区室的细菌产物才被释放。已知I型干扰素(IFN-I)抑制炎性小体活性,这部分地解释了它们长期公认的免疫抑制能力,尽管潜在的机制尚不清楚。由胆固醇产生25-羟基胆固醇(25-HC)的酶Ch 25 h的诱导是IFN-Ⅰ介导的炎性小体抑制的关键组分。Ch 25 h是巨噬细胞中IFN-1刺激的基因,Ch 25 h的缺失导致半胱天冬酶-1活性增加和IL-1 β的释放。25-HC是固醇反应元件结合蛋白(SREBP)胆固醇生物合成途径的有效抑制剂,并且Ch 25 h缺陷型巨噬细胞在TLR刺激后还显示出增加的SREBP途径活性。在巨噬细胞中,SCAP(SREBP活化所需的蛋白质)的缺失导致炎性小体活性降低。基于这些数据,我的目标是表征SREBP通路如何积极调节炎性小体。具体来说,我建议确定SREBP蛋白在增强炎性小体功能的必要性和充分性,并确定它们调节炎性小体激活的步骤(目的1)。我还建议测试的假设,SREBP促进炎症体功能,通过生产胆固醇(目的2)。
项目成果
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