National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
J Biol Chem. 2013 Aug 2;288(31):22426-36. doi: 10.1074/jbc.M113.464883. Epub 2013 Jun 10.
Cyclic di-AMP has been recognized as a ubiquitous second messenger involved in the regulation of bacterial signal transduction. However, little is known about the control of its synthesis and its physiological role in bacteria. In this study, we report a novel mechanism of control of c-di-AMP synthesis and its effects on bacterial growth in Mycobacterium smegmatis. We identified a DisA homolog in M. smegmatis, MsDisA, as an enzyme involved in c-di-AMP synthesis. Furthermore, MsRadA, a RadA homolog in M. smegmatis was found to act as an antagonist of the MsDisA protein. MsRadA can physically interact with MsDisA and inhibit the c-di-AMP synthesis activity of MsDisA. Overexpression of MsdisA in M. smegmatis led to cell expansion and bacterial aggregation as well as loss of motility. However, co-expression of MsradA and MsdisA rescued these abnormal phenotypes. Furthermore, we show that the interaction between RadA and DisA and its role in inhibiting c-di-AMP synthesis may be conserved in bacteria. Our findings enhance our understanding of the control of c-di-AMP synthesis and its physiological roles in bacteria.
环状二腺苷酸（cyclic di-AMP）已被公认为一种普遍存在的第二信使，参与细菌信号转导的调节。然而，关于其合成的控制及其在细菌中的生理作用知之甚少。在本研究中，我们报道了分枝杆菌中环二腺苷酸合成的一种新的调控机制及其对细菌生长的影响。我们在耻垢分枝杆菌中鉴定出一种 DisA 同源物 MsDisA，它是参与 c-di-AMP 合成的酶。此外，还发现分枝杆菌中的 RadA 同源物 MsRadA 作为 MsDisA 蛋白的拮抗剂发挥作用。MsRadA 可以与 MsDisA 发生物理相互作用，并抑制 MsDisA 的 c-di-AMP 合成活性。在耻垢分枝杆菌中过表达 MsdisA 会导致细胞膨胀和细菌聚集以及失去运动性。然而，MsradA 和 MsdisA 的共表达可挽救这些异常表型。此外，我们表明 RadA 和 DisA 之间的相互作用及其在抑制 c-di-AMP 合成中的作用可能在细菌中保守。我们的研究结果增强了我们对 c-di-AMP 合成的调控及其在细菌中生理作用的理解。
