Lab of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China.
Nat Commun. 2024 May 7;15(1):3825. doi: 10.1038/s41467-024-48063-0.
c-di-AMP is an essential and widespread nucleotide second messenger in bacterial signaling. For most c-di-AMP synthesizing organisms, c-di-AMP homeostasis and the molecular mechanisms pertaining to its signal transduction are of great concern. Here we show that c-di-AMP binds the N-acetylglucosamine (GlcNAc)-sensing regulator DasR, indicating a direct link between c-di-AMP and GlcNAc signaling. Beyond its foundational role in cell-surface structure, GlcNAc is attractive as a major nutrient and messenger molecule regulating multiple cellular processes from bacteria to humans. We show that increased c-di-AMP levels allosterically activate DasR as a master repressor of GlcNAc utilization, causing the shutdown of the DasR-mediated GlcNAc signaling cascade and leading to a consistent enhancement in the developmental transition and antibiotic production in Saccharopolyspora erythraea. The expression of disA, encoding diadenylate cyclase, is directly repressed by the regulator DasR in response to GlcNAc signaling, thus forming a self-sustaining transcriptional feedback loop for c-di-AMP synthesis. These findings shed light on the allosteric regulation by c-di-AMP, which appears to play a prominent role in global signal integration and c-di-AMP homeostasis in bacteria and is likely widespread in streptomycetes that produce c-di-AMP.
c-di-AMP 是细菌信号转导中一种必不可少且广泛存在的核苷酸第二信使。对于大多数合成 c-di-AMP 的生物体而言，c-di-AMP 的动态平衡及其信号转导的分子机制是人们关注的重点。在这里，我们发现 c-di-AMP 可以与 N-乙酰葡萄糖胺（GlcNAc）感应调节因子 DasR 结合，这表明 c-di-AMP 与 GlcNAc 信号之间存在直接联系。除了在细胞表面结构中发挥基础性作用之外，GlcNAc 作为一种重要的营养物质和信使分子，从细菌到人类，在调节多种细胞过程方面具有吸引力。我们发现，c-di-AMP 水平的增加可变构激活 DasR，使其成为 GlcNAc 利用的主要阻遏物，从而导致 DasR 介导的 GlcNAc 信号级联失活，并导致红色糖多孢菌的发育转变和抗生素产生一致增强。编码二腺苷酸环化酶的 disA 的表达受到 GlcNAc 信号的直接抑制，因此形成了 c-di-AMP 合成的自我维持转录反馈回路。这些发现揭示了 c-di-AMP 的变构调节作用，它似乎在细菌的全局信号整合和 c-di-AMP 动态平衡中发挥着重要作用，并且在产生 c-di-AMP 的链霉菌中可能广泛存在。
