Role for Lipids in the Maintenance of Chemokine and T-Cell Receptor Signaling

脂质在维持趋化因子和 T 细胞受体信号传导中的作用

• 批准号: 7592059
• 负责人: DENNIS D. TAUB
• 金额: $ 10.03万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592059
• 关键词: Affinity; Antibodies; Attention; Binding; Biology; CCL4 gene; CCR5 gene; CXCL12 gene; CXCR4 gene; Cell Surface Proteins; Cell surface; Cells; Cellular biology; Chemotactic Factors; Cholesterol; Classification; Collection; Data; Epitopes; Family; G-Protein-Coupled Receptors; GPI Membrane Anchors; Giant Cells; Growth Factor Receptors; HIV; Human; Immune; Ligand Binding; Ligation; Lipids; Lymphocyte Activation; Maintenance; Mediating; Membrane Microdomains; Molecular Conformation; Natural regeneration; Neurons; Numbers; Play; Population; Proteins; RNA Interference; Receptor Signaling; Recruitment Activity; Role; Signal Transduction; Signaling Molecule; Sphingolipids; T-Cell Receptor; T-Lymphocyte; Technology; Time; Today; Virus; age related; beta-Cyclodextrins; betadex; chemokine; chemokine receptor; cytokine; flotillin; insight; macrophage; oxidation; receptor; response; trafficking; virus tropism

Lipid rafts play an important role in signal integration and cellular activation of a number of cytokine and growth factor receptors. Flotillin proteins have recently been shown to be recruited to lipid raft microdomains upon cellular activation and have been implicated in neural cell regeneration, receptor signaling and lymphocyte activation. However, little is known about the relevance of the flotillin proteins in T cell responses to chemoattractant stimulation. To this end, cytoplasmic and lipid raft fractions from human T cells were analyzed for flotillin protein redistribution prior to and after CXCL12 stimulation. Flotillin-1 but not flotillin-2 redistributes to lipid rafts upon CXCR4 ligation. Moreover, in CXCL12-treated T cells, flotillin-1 also associates with several raft proteins including LAT, Lck, CD48 and CD11a. In addition, an increase in CXCR4 association with flotillin-1 in lipid rafts was observed after chemokine treatment. RNAi technology was also utilized to inhibit the expression of flotillin-1 resulting in an inhibition of CXCL12-mediated signaling, function and CXCR4 recruitment into lipid rafts. Together, these data suggest that the association of flotillin-1 with lipid raft during chemokine exposure may play an important role in chemokine receptor recruitment to and signaling in lipid rafts and possibly in leading edge formation. Overall, we believe that a greater understanding of the various signaling and cell surface proteins associated with lipid rafts may provide insight into age-related alterations in cell signaling and trafficking.

脂筏在信号整合和细胞内多种细胞因子和生长因子受体的活化中起重要作用。Flotillin蛋白最近已被证明在细胞活化后被募集到脂筏微结构域，并且已经涉及神经细胞再生、受体信号传导和淋巴细胞活化。 然而，很少有人知道的相关性的flotillin蛋白的T细胞反应的化学引诱物刺激。 为此，在CXCL 12刺激之前和之后，分析来自人T细胞的细胞质和脂筏级分的flotillin蛋白质再分布。在CXCR 4连接后，Flotillin-1而不是Flotillin-2重新分布到脂筏。 此外，在CXCL 12处理的T细胞中，flotillin-1还与包括LAT、Lck、CD 48和CD 11 a在内的几种筏蛋白结合。 此外，在趋化因子处理后，观察到CXCR 4与脂筏中的flotillin-1的结合增加。RNAi技术也被用于抑制flotillin-1的表达，从而抑制CXCL 12介导的信号传导、功能和CXCR 4向脂筏中的募集。总之，这些数据表明，在趋化因子暴露过程中，flotillin-1与脂筏的关联可能在趋化因子受体募集和脂筏信号传导中以及可能在前缘形成中发挥重要作用。 总体而言，我们认为，更好地了解与脂筏相关的各种信号和细胞表面蛋白质，可能会提供洞察细胞信号和贩运的年龄相关的变化。