Discovery of cGAS-like signaling enzymes in innate immunity and disease

项目摘要 人类细胞使用被称为“rna第二信使”的信号来刺激免疫反应并防止 疾病。这些信号是对病原体感染和细胞应激反应产生的，对 控制蜂窝通信。最近的证据表明，RNA第二信使信号 受酶控制的环状GMP-AMP合成酶(CGAS)是免疫应答的关键组成部分 许多类型的癌症，以及从这些自然信号开发出来的药物类似物正在迅速出现 前景看好的新疗法。这些药物强大的抗肿瘤潜力说明了发现的重要性。 以及对自然产生的RNA第二信使信号的机械理解。 令人惊讶的是，我们的工作揭示了cGAS是我们命名的信号酶广泛家族的一部分 CGAS/DncV样核苷酸转移酶(CD-NTase)和许多RNA第二信使途径 在人类生物学中仍有待发现。潜在的人类CD-NTase包括未鉴定的免疫性cGAs- 类似的受体以前被认为是癌症中频繁突变的基因。我们的结果表明，RNA 第二信使信号通路是一个新的丰富的研究领域，并可能影响许多领域的基础 人类生物学和疾病。我们开发了一种创新的方法来揭示这些 并发现负责信号传递的生物和天然产物。 我们提出的研究将提供对控制rna的第二种酶的新的详细的理解。 信使信使信号，并使发现全新类别的RNA信号。具体地说，建议的 实验将使用全王国的CD-NTase酶的分析来确定特定RNA的机制 产物合成、X射线结晶学研究后生动物CD-NTase的结构和分子基础 功能，以及一套创新的细胞生物学实验，使用新发现的CD-NTase RNA信号用于 直接细胞刺激和化学蛋白质组学。我们的实验将定义新发现的 并解释了允许RNA第二信使 控制下游的细胞反应。

Project Summary Human cells use signals called "RNA second messengers" to stimulate the immune response and prevent disease. These signals are produced in response to pathogen infection and cellular stress, and are important for controlling cellular communication. Recent evidence demonstrates that RNA second messenger signaling controlled by the enzyme cyclic GMP–AMP synthase (cGAS) is a critical component of the immune response to many types of cancer, and drug analogues developed from these natural signals are rapidly emerging as promising new treatments. The potent antitumor potential of these drugs illustrates the importance of discovery and mechanistic understanding of naturally occurring RNA second messenger signals. Surprisingly, our work has revealed that cGAS is part of a broad family of signaling enzymes we named cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzymes, and many RNA second messenger pathways remain to be discovered in human biology. Potential human CD-NTases include uncharacterized immune cGAS- like receptors previously implicated as genes frequently mutated in cancer. Our results demonstrate that RNA second messenger signaling pathways are a new rich area of research and likely impact many areas of basic human biology and disease. We have developed an innovative approach to uncover the function of these enzymes and discover the biology and natural products responsible for signaling. Our proposed research will provide a new detailed understanding of the enzymes that control RNA second messenger signaling and enable discovery of entirely new classes of RNA signals. Specifically, the proposed experiments will use kingdom-wide analysis of CD-NTase enzymes to determine the mechanism of specific RNA product synthesis, X-ray crystallography to define the structural and molecular basis of metazoan CD-NTase function, and an innovative set of cell biology experiments using newly identified CD-NTase RNA signals for direct cell stimulation and chemical-proteomics. Our experiments will define the function of newly discovered cGAS-like enzymes in human biology and explain the molecular rules that allow RNA second messengers to control downstream cellular responses.