Brogan Anna P, Bardetti Paola, Rojas Enrique R, Rudner David Z
Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Department of Biology, New York University, New York, NY, USA.
Nat Microbiol. 2025 Jun 17. doi: 10.1038/s41564-025-02027-2.
Cyclic-di-AMP (c-di-AMP) is an essential second messenger in Bacillus subtilis and many other Gram-positive bacteria. Work over the past decade has revealed that this cyclic nucleotide controls cation and osmolyte transporters, leading to the hypothesis that c-di-AMP regulates cytoplasmic turgor pressure. Although the targets of c-di-AMP are well established, the signals that control the levels of this second messenger and the factors that transduce these signals are unknown. Here we report that c-di-AMP levels are modulated by the cyclase regulator CdaR in response to cell wall defects. We further demonstrate that changing the levels of c-di-AMP alters turgor pressure. Our data support a model in which CdaR senses defects in the cell wall and activates c-di-AMP synthesis in response. The increase in c-di-AMP reduces turgor, preventing lysis and enabling fortification of the peptidoglycan meshwork. Thus, a central function of c-di-AMP is to control cellular turgor in response to envelope defects.
环二腺苷酸（c-di-AMP）是枯草芽孢杆菌及许多其他革兰氏阳性菌中的一种重要第二信使。过去十年的研究表明，这种环核苷酸可调控阳离子和渗透溶质转运蛋白，由此提出了c-di-AMP调节细胞质膨压的假说。尽管c-di-AMP的作用靶点已明确，但控制这种第二信使水平的信号以及转导这些信号的因子尚不清楚。在此，我们报告环化酶调节因子CdaR会响应细胞壁缺陷来调节c-di-AMP的水平。我们进一步证明，改变c-di-AMP的水平会改变膨压。我们的数据支持一种模型，即CdaR感知细胞壁缺陷并相应激活c-di-AMP的合成。c-di-AMP的增加会降低膨压，防止细胞裂解，并使肽聚糖网络得到强化。因此，c-di-AMP的核心功能是响应包膜缺陷来控制细胞膨压。
