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

泛素和泛素样分子在直接抗原呈递中的作用

基本信息

批准号：
10092081
负责人：
Brian Paul Dolan
金额：
$ 35.22万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-20 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092081
关键词：
Address Antigen Presentation Antigen Presentation Pathway Antigen Targeting Antigens Binding Biochemical CD8-Positive T-Lymphocytes CD8B1 gene Cell surface Cells Cellular biology Chemicals Complex Coupling Cullin Proteins Cytotoxic T-Lymphocytes Data Deubiquitinating Enzyme Disease Elements Ensure Enzymes Genes Genetic Genome Histocompatibility Antigens Class I Immune system Infection Libraries Major Histocompatibility Complex Mediating Metabolic Pathway Minor Modeling Molecular Target Mus Oncogenic Outcome Pathway interactions Peptides Physiological Play Process Protein Biosynthesis Protein Precursors Proteins Reaction Research Personnel Ribosomal Proteins Ribosomes Role Small Interfering RNA Source Specificity Surface T cell response Testing Translating Translations Tumor Antigens Ubiquitin Ubiquitin Like Proteins Ubiquitination Viral Viral Antigens Viral Proteins Virus Diseases Work cancer type cell killing cell transformation cell type chemical genetics combat cytotoxic CD8 T cells genetic inhibitor immunogenic immunoreaction in vivo inhibitor/antagonist interest knock-down member multicatalytic endopeptidase complex neoplastic cell protein degradation response scaffold tumor ubiquitin ligase ubiquitin-protein ligase ubiquitin-specific protease

项目摘要

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.

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。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Variations in Cell Surface ACE2 Levels Alter Direct Binding of SARS-CoV-2 Spike Protein and Viral Infectivity: Implications for Measuring Spike Protein Interactions with Animal ACE2 Orthologs.

DOI：
10.1128/jvi.00256-22
发表时间：
2022-09-14
期刊：
JOURNAL OF VIROLOGY
影响因子：
5.4
作者：
Kazemi, Soheila;Lopez-Munoz, Alberto Domingo;Holly, Jaroslav;Jin, Ling;Yewdell, Jonathan W.;Dolan, Brian P.
通讯作者：
Dolan, Brian P.

Direct Conjugation of NEDD8 to the N-Terminus of a Model Protein Can Induce Degradation.

NEDD8与模型蛋白的N末端的直接结合可以诱导降解。

DOI：
10.3390/cells10040854
发表时间：
2021-04-09
期刊：
Cells
影响因子：
6
作者：
Vijayasimha K;Tran MV;Leestemaker-Palmer AL;Dolan BP
通讯作者：
Dolan BP

MLN4924 Inhibits Defective Ribosomal Product Antigen Presentation Independently of Direct NEDDylation of Protein Antigens.

DOI：
10.4049/jimmunol.2100584
发表时间：
2022-05-15
期刊：
JOURNAL OF IMMUNOLOGY
影响因子：
4.4
作者：
Vijayasimha, Kartikeya;Leestemaker-Palmer, Amy L.;Gibbs, James S.;Yewdell, Jonathan W.;Dolan, Brian P.
通讯作者：
Dolan, Brian P.

Quantitating MHC Class I Ligand Production and Presentation Using TCR-Like Antibodies.

使用 TCR 样抗体定量 MHC I 类配体的产生和呈现。