Regulation of T Cell Responses by Chaperone-Mediated Autophagy

分子伴侣介导的自噬对 T 细胞反应的调节

基本信息

批准号：
9279041
负责人：
Fernando Macian
金额：
$ 41.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279041
关键词：
Address Affect Amino Acids Antigens Autophagocytosis Biochemical CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Cellular Metabolic Process Complex Data Development Ensure Enzymes Generations Goals Helper-Inducer T-Lymphocyte Homeostasis Immune response Immunization Listeriosis Lysosomes Mediating Membrane Membrane Proteins Modeling Molecular Molecular Chaperones Nutrient Organelles Pathway interactions Play Process Protein Biosynthesis Proteins Proteome Receptor Signaling Recycling Regulation Regulatory Pathway Role Signal Pathway Signal Transduction Stimulus Stress System T cell regulation T cell response T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Translating Ubiquitin adaptive immune response extracellular in vivo in vivo Model inhibitor/antagonist limbic system-associated membrane protein lysosomal proteins mouse model multicatalytic endopeptidase complex novel novel therapeutic intervention pathogen protein degradation receptor response retinoic acid receptor alpha ubiquitin-protein ligase

项目摘要

Abstract T cell activation requires a tight regulation of positive and negative modulators of signaling pathways downstream of the T cell receptor (TCR). Degradation of specific proteins following TCR engagement is an essential regulatory mechanism that ensures efficient T cell responses. Chaperone-mediated autophagy (CMA) is an inducible form of autophagy that selectively degrades soluble cytosolic proteins that present a pentapetide targeting motif. The ability of CMA to selectively degrade proteins makes this type of autophagy a candidate to contribute to the regulation of the levels of specific signaling intermediates in response to different stimuli. We have recently shown that CMA is activated in CD4+ T cells in response to TCR engagement to regulate signaling pathways downstream of the TCR by selectively targeting inhibitors of TCR signaling for degradation in the lysosomes. In this proposal we intend to elucidate the molecular mechanisms that explain how this specific form of autophagy modulates CD4+ T cell function and characterize how CMA regulates adaptive immune responses in vivo. Our overall goal is to define CMA as a novel regulatory mechanism of T cell activation and to determine the possibility of targeting CMA to modulate T cell responses.

抽象的 T 细胞激活需要信号通路正负调节剂的严格调节 T 细胞受体 (TCR) 的下游。 TCR 参与后特定蛋白质的降解是一种确保有效 T 细胞反应的重要调节机制。分子伴侣介导的自噬（CMA）是自噬的一种诱导形式，选择性降解呈现五肽的可溶性胞质蛋白目标主题。 CMA 选择性降解蛋白质的能力使这种类型的自噬成为有助于调节特定信号中间体的水平以响应不同的刺激。我们最近表明，CMA 在 CD4+ T 细胞中被激活，以响应 TCR 参与来调节信号传导通过选择性靶向 TCR 信号传导抑制剂以降解 TCR 下游途径溶酶体。在这个提案中，我们打算阐明分子机制，解释这种特定形式如何自噬调节 CD4+ T 细胞功能并表征 CMA 如何调节适应性免疫反应体内。我们的总体目标是将 CMA 定义为一种新型的 T 细胞激活调节机制，并确定靶向 CMA 调节 T 细胞反应的可能性。