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.

项目摘要/摘要 CGAS-CGAMP-sting DNA感应途径已成为关键的先天免疫响应， 对于抗病毒免疫学很重要，有助于自身免疫性疾病，并介导抗毒液的各个方面 免疫力。CGAMP是一种环状二核苷酸第二信使，无法单独进入或退出单元，因为 其强烈的负电荷，导致绝大多数CGAMP生物学研究仅关注 CGAMP的细胞内动力学。但是，最近的进步已经确定了细胞外CGAMP 是一种潜在的“免疫递质”，可以通过许多跨膜通道进口 在距离上刺激信号。一个基本问题是CGAMP如何退出细胞细胞外 免疫递质，但CGAMP输出的分子机制是完全未知的。 我们发现，CGAMP从活细胞中积极出口，与细胞死亡无关。我们有 将ATP结合盒（ABC）转运蛋白ABCC1/MRP1识别为介导活动CGAMP的通道 出口。我们的研究将探讨ABCC1介导的CGAMP的细胞生物学和生化机制 导出，并将在CGAS依赖性自身免疫的鼠标模型中测试CGAMP导出的体内功能 疾病。通过定义CGAMP出口的新型机制，我们的研究将对 旨在阻止自身免疫性疾病中CGA反应或增强肿瘤刺激信号的治疗剂。