总结核苷酸衍生的第二信使存在于生命的所有域中。在原核生物中,它们的大部分功能与一般生活方式和代谢适应有关,通常响应环境的物理参数波动。在过去的二十年里,环状di-AMP已成为许多原核谱系中重要的信号核苷酸,包括Firmicutes,放线菌,和蓝细菌。环状di-AMP的缺乏和过度生产都会影响利用环状di-AMP的原核生物的生存能力,这一事实突显了其重要性。并且它在真核生物中产生强烈的先天免疫反应。在产生第二信使的细菌中,环状di-AMP的大多数分子靶标与细胞体积控制有关。此外,其他证据将第二信使与细胞壁重塑联系起来,DNA损伤修复,孢子形成,中枢代谢,和糖原周转的调节。在这次审查中,我们需要一个生化的,定量方法来解决由环状di-AMP直接调节的主要细胞过程,并表明这些过程非常相关,需要调节与环状di-AMP结合的相似的一组蛋白质。总之,我们认为,循环di-AMP是细胞体积的主要调节因子,其他细胞过程可以通过此核心功能与循环di-AMP连接。我们进一步强调了循环di-AMP领域必须发展的重要方向,以充分了解循环di-AMP信令网络以及为什么某些过程被调节,而其他人不是。
SUMMARYNucleotide-derived second messengers are present in all domains of life. In prokaryotes, most of their functionality is associated with general lifestyle and metabolic adaptations, often in response to environmental fluctuations of physical parameters. In the last two decades, cyclic di-AMP has emerged as an important signaling nucleotide in many prokaryotic lineages, including Firmicutes, Actinobacteria, and Cyanobacteria. Its importance is highlighted by the fact that both the lack and overproduction of cyclic di-AMP affect viability of prokaryotes that utilize cyclic di-AMP, and that it generates a strong innate immune response in eukaryotes. In bacteria that produce the second messenger, most molecular targets of cyclic di-AMP are associated with cell volume control. Besides, other evidence links the second messenger to cell wall remodeling, DNA damage repair, sporulation, central metabolism, and the regulation of glycogen turnover. In this review, we take a biochemical, quantitative approach to address the main cellular processes that are directly regulated by cyclic di-AMP and show that these processes are very connected and require regulation of a similar set of proteins to which cyclic di-AMP binds. Altogether, we argue that cyclic di-AMP is a master regulator of cell volume and that other cellular processes can be connected with cyclic di-AMP through this core function. We further highlight important directions in which the cyclic di-AMP field has to develop to gain a full understanding of the cyclic di-AMP signaling network and why some processes are regulated, while others are not.