Mechanisms of cGAMP export

cGAMP 输出机制

• 批准号: 10190600
• 负责人: Daniel B Stetson
• 金额: $ 26.48万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-03 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190600
• 关键词: ABCC1 gene; ATP-Binding Cassette Transporters; Address; Antiviral Response; Autoimmune Diseases; Autoimmunity; Biochemical; Biological; Biological Assay; Biological Process; Biology; Cell Death; Cells; Charge; DNA; Dinucleoside Phosphates; Human; In Vitro; Innate Immune Response; Kinetics; Mediating; Molecular; Mus; Pathway interactions; Periodicity; Regulation; Role; Second Messenger Systems; Signal Transduction; Stimulator of Interferon Genes; Testing; Therapeutic; Tumor Immunity; antiviral immunity; extracellular; gain of function; in vivo; in vivo evaluation; insight; loss of function; mouse model; neoplastic cell; novel; overexpression; pseudotoxoplasmosis syndrome; response; tumor; vesicle transport

Project Summary/Abstract The cGAS-cGAMP-STING DNA sensing pathway has emerged as a key innate immune response that is important for antiviral immunity, contributes to autoimmune diseases, and mediates aspects of antitumor immunity. cGAMP is a cyclic dinucleotide second messenger that cannot enter or exit cells on its own because of its strong negative charge, leading the vast majority of studies of cGAMP biology to focus solely on intracellular dynamics of cGAMP. However, very recent advances have established that extracellular cGAMP is a potent “immunotransmitter” that can be imported through a number of transmembrane channels to mediate STING signaling over a distance. A fundamental question is how cGAMP exits cells to become an extracellular immunotransmitter, but the molecular mechanisms of cGAMP export are completely unknown. We have found that cGAMP is actively exported from live cells, independent of cell death. We have identified the ATP-binding cassette (ABC) transporter ABCC1/MRP1 as a channel that mediates active cGAMP export. Our studies will explore the cell biological and biochemical mechanisms of ABCC1-mediated cGAMP export, and will test the in vivo function of cGAMP export in a mouse model of cGAS-dependent autoimmune disease. By defining a novel mechanism of cGAMP export, our studies will have important implications for therapeutics that aim to block cGAS responses in autoimmune disease or enhance STING signaling in tumors.

项目概要/摘要 cGAS-cGAMP-STING DNA 传感通路已成为一种关键的先天免疫反应， 对于抗病毒免疫很重要，有助于自身免疫性疾病，并介导抗肿瘤方面的作用 cGAMP 是一种环状二核苷酸第二信使，不能自行进入或退出细胞，因为 其强大的负电荷，导致绝大多数 cGAMP 生物学研究仅关注 然而，最近的进展已经确定了细胞外 cGAMP。 是一种有效的“免疫递质”，可以通过多种跨膜通道输入来介导 远距离 STING 信号传导的一个基本问题是 cGAMP 如何离开细胞成为细胞外信号。 免疫递质，但 cGAMP 输出的分子机制完全未知。 我们发现 cGAMP 从活细胞中主动输出，与细胞死亡无关。 确定 ATP 结合盒 (ABC) 转运蛋白 ABCC1/MRP1 是介导活性 cGAMP 的通道 我们的研究将探索ABCC1介导的cGAMP的细胞生物学和生化机制。 导出，并将在 cGAS 依赖性自身免疫小鼠模型中测试 cGAMP 导出的体内功能 通过定义 cGAMP 输出的新机制，我们的研究将对疾病产生重要影响。 旨在阻断自身免疫性疾病中的 cGAS 反应或增强肿瘤中的 STING 信号传导的疗法。