The Role of Ubiquitin and Ubiquitin-Like Molecules in Direct Antigen Presentation

项目摘要 说明.免疫系统必须消除身体的细胞，这些细胞因此而患病 细胞内感染或致癌转化。CD8+细胞毒性T细胞负责完成这一过程。 必须能够区分健康细胞和病变细胞。类主要组织相容性复合 I（MHC I类）分子存在于大多数有核细胞上，并负责在细胞内呈递抗原。 细胞表面进行CD8 + T细胞检查。为了呈递抗原，MHC I类途径依赖于 与降解的细胞蛋白质产生的短肽结合。当源蛋白与 疾病（如病毒蛋白或肿瘤相关蛋白）特异性CD8 + T细胞将识别所述肽。 MHC I类复合体并杀死细胞。由于肽在该反应中提供了最终的特异性，我们 有兴趣了解这些肽是如何产生的。我们的数据表明， 在它们合成后迅速降解的蛋白质（称为缺陷核糖体蛋白质或DRiP）负责 有效地产生肽的供应。这项建议旨在确定哪些细胞代谢 途径用于指导DRiPs的快速降解，并确定DRiPs是否是必需的。 生理相关的设置。我们关注的是泛素结合途径，如泛素偶联 与蛋白质降解密切相关。泛素样蛋白（UBLs）也可能在直接免疫中发挥作用。 抗原呈递这项提议的具体目的是确定泛素修饰酶如何 Usp14与抗原呈递机制相互作用，理解为什么泛素样结合 分子Nedd8是DRiP抗原呈递所必需的，并确定哪些E3泛素连接酶是 DRiP抗原呈递所必需的。

Project Summary DESCRIPTION. 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. Ubiquitin-like proteins (UBLs) may also play a role in direct antigen presentation. The Specific Aims of this proposal are to identify how the ubiquitin-modifying enzyme Usp14 interacts with the antigen presentation machinery, understand why conjugation of the ubiquitin-like molecule Nedd8 is necessary for DRiP antigen presentation, and determine which E3 ubiquitin ligases are necessary for DRiP antigen presentation.