Exploring cyclic di-nucleotide signaling across the tree of life

摘要：探索生命之树上的环二核苷酸信号 所有生物都利用将外部感觉系统与表型联系起来的分子调控机制 输出。环二核苷酸(CDN)第二信使分子就是这样一个保守的基本系统 从细菌到人类。在细菌中，cdns调节许多表型，包括但不限于生物膜。 形成、运动、毒力、胁迫反应、DNA修复、细胞形态和噬菌体防御。真核生物 也利用CDN进行复杂的多细胞发育途径和天然免疫系统的激活 动员抗病毒和抗癌免疫反应。尽管CDN在全球范围内发挥着如此重要的作用 系统发育树，它们只在细菌中被深入研究了大约15年，而且只有几个 在真核系统中生存了数年。CDN信令的多样性等问题依然存在 系统，诱导它们产生的环境信号，感知和 对它们的反应、CDN调节的表型以及这些信号系统的适应性益处。我的 实验室从2008年开始研究CDN信令，并做出了根本性的贡献 来到这片田野。我们的研究已经阐明了转录和转录后机制， CDN环状双GMP调控霍乱弧菌基因表达。我们也有很大的 扩大了我们对环二核苷酸控制的表型的理解，包括DNA修复、应激 响应值和细胞曲率。我们发现并鉴定了第一个环状病毒细菌蛋白受体 GMP-AMP是霍乱弧菌编码的一种磷脂酶，我们称之为CapV。我们对新的CDN的搜索导致了我们 发现酿酒酵母合成环状二UMP，首次检测到嘧啶CDN 在活体内，对热休克的反应。我们建议通过定义循环来回答关于CDN的基本问题 霍乱弧菌Di-GMP基因调控和表型调控及其调控网络的破译 影响细菌的健康。我们的研究还将进一步表征我们拥有的新的环状GMP-AMP途径 在霍乱弧菌中发现，并将我们对循环GMP-AMP样信号通路的研究扩展到其他 细菌。最后，我们将鉴定酿酒酵母中的环二UMP合成酶，确定这一CDN的影响 在酵母生理学方面，并在其他真核细胞中寻找循环双UMP信号。我们的探索 将细菌跨越到真核生物将对回答关于 CDN信令。

Summary: Exploring cyclic di-nucleotide signaling across the tree of life All organisms utilize molecular regulatory mechanisms connecting external sensory systems to phenotypic output. Cyclic di-nucleotide (cdN) second messenger molecules are one such fundamental system conserved from bacteria to humans. In bacteria, cdNs regulate numerous phenotypes including but not limited to biofilm formation, motility, virulence, stress responses, DNA repair, cell morphology, and phage defense. Eukaryotes also utilize cdNs for complex multicellular development pathways and activation of the innate immune system to mobilize anti-viral and anti-cancer immune responses. Although cdNs play such important functions across the phylogenetic tree, they have only been intensively studied for about 15 years in bacteria and only a few years in eukaryotic systems. There remain many outstanding questions such as the diversity of cdN signaling systems, the environmental signals that induce their production, the molecular mechanisms that sense and respond to them, the phenotypes cdNs regulate, and the adaptive benefit of such signaling systems. My laboratory has studied cdN signaling since its inception in 2008, and we have made fundamental contributions to this field. Our research has elucidated both transcriptional and post-transcriptional mechanisms by which the cdN cyclic di-GMP regulates gene expression in the bacterial pathogen Vibrio cholerae. We have also greatly expanded our understanding of the phenotypes controlled by cyclic di-GMP including DNA repair, stress responses, and cell curvature. We discovered and characterized the first bacterial protein receptor of cyclic GMP-AMP, a phospholipase encoded by V. cholerae we named CapV. Our search for novel cdNs led us to discover that the yeast Saccharomyces cerevisiae synthesizes cyclic di-UMP, the first pyrimidine cdN detected in vivo, in response to heat shock. We propose to answer fundamental questions about cdNs by defining cyclic di-GMP gene regulation and phenotypic control in V. cholerae and deciphering how such regulatory networks impact bacterial fitness. Our studies will also further characterize the novel cyclic GMP-AMP pathway we have discovered in V. cholerae and extend our studies of cyclic GMP-AMP-like signaling pathways into other bacteria. Finally, we will identify the cyclic di-UMP synthase in S. cerevisiae, determine the impact of this cdN on yeast physiology, and search for cyclic di-UMP signaling in other eukaryotic cells. Our explorations spanning bacteria to eukaryotes will make significant contributions to answering fundamental questions about cdN signaling.