National Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
Nucleic Acids Res. 2018 Apr 20;46(7):3595-3611. doi: 10.1093/nar/gky146.
Cyclic di-GMP (c-di-GMP) is a global signaling molecule that widely modulates diverse cellular processes. However, whether or not the c-di-GMP signal participates in regulation of bacterial antioxidant defense is unclear, and the involved regulators remain to be explored. In this study, we characterized HpoR as a novel c-di-GMP effective transcription factor and found a link between the c-di-GMP signal and the antioxidant regulation in Mycobacterium smegmatis. H2O2 stress induces c-di-GMP accumulation in M. smegmatis. High level of c-di-GMP triggers expression of a redox gene cluster, designated as hpoR operon, which is required for the mycobacterial H2O2 resistance. HpoR acts as an inhibitor of the hpoR operon and recognizes a 12-bp motif sequence within the upstream regulatory region of the operon. c-di-GMP specifically binds with HpoR at a ratio of 1:1. Low concentrations of c-di-GMP stimulate the DNA-binding activity of HpoR, whereas high concentrations of the signal molecule inhibit the activity. Strikingly, high level of c-di-GMP de-represses the intracellular association of HpoR with the regulatory region of the hpoR operon in M. smegmatis and enhances the mycobacterial H2O2 resistance. Therefore, we report a novel c-di-GMP effective regulator in mycobacteria, which extends the second messenger's function to bacterial antioxidant defense.
环二鸟苷酸（c-di-GMP）是一种广泛调节多种细胞过程的全局信号分子。然而，c-di-GMP 信号是否参与细菌抗氧化防御的调节尚不清楚，涉及的调节剂仍有待探索。在本研究中，我们将 HpoR 鉴定为一种新型 c-di-GMP 有效转录因子，并发现 c-di-GMP 信号与分枝杆菌抗氧化调节之间存在联系。H2O2 应激诱导 M. smegmatis 中 c-di-GMP 的积累。高水平的 c-di-GMP 触发了一个称为 hpoR 操纵子的氧化还原基因簇的表达，该操纵子是分枝杆菌 H2O2 抗性所必需的。HpoR 作为 hpoR 操纵子的抑制剂，识别操纵子上游调控区的 12 个碱基对序列。c-di-GMP 与 HpoR 以 1:1 的比例特异性结合。低浓度的 c-di-GMP 刺激 HpoR 的 DNA 结合活性，而高浓度的信号分子则抑制该活性。引人注目的是，高水平的 c-di-GMP 解除了 M. smegmatis 中 HpoR 与 hpoR 操纵子调控区的细胞内关联，并增强了分枝杆菌的 H2O2 抗性。因此，我们在分枝杆菌中报告了一种新型的 c-di-GMP 有效调节剂，该调节剂将第二信使的功能扩展到细菌抗氧化防御。
