The Expanded Repertoire of cGAMP Signal Transduction During Innate Immune Responses

项目总结/摘要 致癌DNA病毒的感染占人类癌症的12%，并且是导致癌症的主要原因。 死亡率和发病率。治疗病毒感染的新疗法的开发 将大大受益于宿主对这种感染性损伤的反应的详细了解。的 免疫系统抵抗病毒感染的能力通常是通过复杂的 与病毒核酸结合的蛋白质。在对病毒DNA的反应中，宿主蛋白质环GMP- AMP（cGAMP）合酶（cGAS）产生信号核苷酸cGAMP，其引发宿主炎症 通过与干扰素基因刺激蛋白（STING）结合来清除感染。然而，第二 信使信号转导系统通常依赖于多种蛋白质受体来驱动细胞应答。 cGAMP是否可以在STING激活之外发挥作用以限制病毒感染和肿瘤发生仍然存在 大部分未知。最近的研究表明，cGAS和STING可以对细胞增殖具有非重叠的影响。 感染结果，这表明cGAS在响应病毒感染中除了信号传导外还起着多种作用 通过STING。为了系统地解决这一假设，我们已经产生了包被在cGAMP中的珠， 能够从细胞提取物中分离cGAMP结合蛋白。利用这种方法，我们发现了两个新的 除了STING之外的蛋白质可以与cGAMP结合。这些新的cGAMP结合蛋白具有已知的作用， 调节宿主对感染的反应所涉及的细胞过程，包括细胞如何产生能量 以及生物合成的基本组成部分，这些基本方面的细胞生理学， 以便于复制。在这里，我建议利用结构-功能分析结合生物化学和 感染模型来询问这些以前未被识别的cGAMP结合的生物学相关性， 蛋白质，并详细说明其对病毒限制的影响。这些研究的结果将大大有助于 宿主免疫系统可以限制病毒感染和肿瘤发生的机制， 防治传染病和恶性疾病的新的治疗策略。

PROJECT SUMMARY/ABSTRACT Infections with oncogenic, DNA viruses account for twelve percent of human cancers and are a major cause of mortality and morbidity throughout the world. The development of new therapeutics to treat viral infections would significantly benefit from a detailed understanding of the host response to this infectious insult. The ability of the immune system to counteract viral infection is often mediated through a sophisticated repertoire of proteins that bind to viral nucleic acids. In response to DNA derived from viruses, the host protein cyclic GMP- AMP (cGAMP) Synthase (cGAS) produces the signaling nucleotide cGAMP, which initiates host inflammation to clear infection by binding to the protein Stimulatory of Interferon Genes (STING). However, second messenger signal transduction systems often rely on a variety of protein receptors to drive cellular responses. Whether cGAMP can function beyond STING activation to restrict viral infection and oncogenesis remains largely unknown. Recent studies have shown that cGAS and STING can have non-overlapping effects on infection outcome, suggesting that cGAS plays multiple roles in response to viral infection beyond signaling through STING. To systematically address this hypothesis, we have generated beads coated in cGAMP that are able to isolate cGAMP-binding proteins from cell extracts. Using this method, we have identified two new proteins other than STING that can bind to cGAMP. These novel cGAMP binding proteins have known roles in regulating cellular processes involved in the host response to infection including how the cell produces energy as well as biosynthetic building blocks, fundamental aspects of cellular physiology that viruses rely upon in order to facilitate replication. Here, I propose to utilize structure-function analysis coupled with biochemical and infection models to interrogate the biological relevance of these previously unrecognized cGAMP-binding proteins and detail their effects on viral restriction. The findings from these studies will significantly inform the mechanisms by which the host immune system can restrict viral infection and oncogenesis and may provide new therapeutic strategies to combat infectious and malignant diseases.