Ubiquitin conjugation and direct MHC class I antigen presentation

泛素结合和直接 MHC I 类抗原呈递

基本信息

批准号：
8880646
负责人：
Brian Paul Dolan
金额：
$ 35.16万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880646
关键词：
Address Antigen Presentation Antigen Presentation Pathway Antigens Binding Biochemical CD8B1 gene Cell surface Cells Chemicals Clinic Complex Coupling Cullin Proteins Cytotoxic T-Lymphocytes Data Deubiquitinating Enzyme Development Disease Elements Ensure Enzymes Excision Genes Genome Health Histocompatibility Antigens Class I Immune Immune system Infection Libraries Major Histocompatibility Complex Mediating Metabolic Pathway Modeling Molecular Target Mus Oncogenic Outcome Pathway interactions Peptides Physiological Process Protein Biosynthesis Protein Precursors Proteins Publishing Reaction Research Personnel Ribosomal Proteins Small Interfering RNA Source Specificity Surface T cell response T-Lymphocyte Testing Translating Translations Ubiquitin Ubiquitin Like Proteins Ubiquitination Viral Proteins Virus Diseases Work cancer type cell killing cell transformation cell type chemical genetics combat genetic inhibitor immunogenic inhibitor/antagonist interest member neoplastic cell neuronal cell body protein degradation response scaffold small molecule libraries tumor ubiquitin isopeptidase ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The immune system must eliminate cells of the body that have become diseased as the result of intracellular infection or oncogenic transformation. CD8+ cytotoxic T cells are responsible for completing this task and must be able to distinguish healthy cells from diseased ones. Major Histocompatibility Complex Class I (MHC class I) molecules are present on most nucleated cells and are responsible for presenting antigen at the cell surface for CD8+ T cell inspection. In order to present antigen, the MHC class I pathway relies on binding to short peptides, created from degraded cellular proteins. When the source protein is associated with a disease (such as a viral protein or tumor associated protein) specific CD8+ T cells will recognize the peptide- MHC class I complex and kill the cell. Because the peptide provides the ultimate specificity in this reaction, we are interested in understanding how these peptides are created. Our data indicates that proteins which are rapidly degraded following their synthesis (termed Defective Ribosomal Proteins or DRiPs) are responsible for efficiently generating a supply of peptides. This proposal seeks to determine which cellular metabolic pathways are used to direct the rapid degradation of DRiPs and to determine if DRiPs are necessary in physiologically relevant settings. We are focusing on the ubiquitin conjugation pathway, as ubiquitin coupling is intimately associated with protein degradation. The Specific Aims of this proposal are to determine which E3 ubiquitin ligases are necessary for DRiP antigen presentation, understand why conjugation of the ubiquitin-like molecule Nedd8 is necessary for DRiP antigen presentation, and identify and characterize chemical inhibitors of DRiP antigen presentation that target de-ubiquitinating enzymes (DUBs).

描述（由申请人提供）：免疫系统必须消除由于细胞内感染或致癌性转化而患病的人体细胞。 CD8+细胞毒性T细胞负责完成此任务，并且必须能够将健康细胞与患病细胞区分开。主要的组织相容性复合物I类（MHC I类）分子存在于大多数核细胞上，并负责在细胞表面呈现抗原进行CD8+ T细胞检查。为了呈现抗原，MHC I类途径依赖于由降解的细胞蛋白产生的短肽的结合。当源蛋白与疾病（例如病毒蛋白或肿瘤相关蛋白）相关时 CD8+ T细胞将识别肽MHC I类配合物并杀死细胞。由于肽在此反应中提供了最终特异性，因此我们有兴趣了解如何创建这些肽。我们的数据表明，其合成后迅速降解的蛋白质（称为缺陷核糖体蛋白或滴水）负责有效产生肽的供应。该建议旨在确定哪种细胞代谢途径用于指导滴水的快速降解，并确定在生理上相关的环境中是否需要滴水。我们专注于泛素结合途径，因为泛素偶联与蛋白质降解密切相关。该提案的具体目的是确定哪种E3泛素连接酶对于滴注抗原表现是必要的，请理解为什么要偶联的泛素样分子NEDD8的结合对于滴水抗原呈递是必要的，以及识别和表征和表征靶向去泛素化剂的滴注抗原呈现的化学抑制剂（DUB）。