Martin Julia E, Lisher John P, Winkler Malcolm E, Giedroc David P
Department of Chemistry, Indiana University, Bloomington, IN, 47405-7102, USA.
Graduate Program in Biochemistry Indiana University, Bloomington, IN, 47405, USA.
Mol Microbiol. 2017 Apr;104(2):334-348. doi: 10.1111/mmi.13630. Epub 2017 Feb 21.
Manganese (Mn) is an essential micronutrient and required cofactor in bacteria. Despite its importance, excess Mn can impair bacterial growth, the mechanism of which remains largely unexplored. Here, we show that proper Mn homeostasis is critical for cellular growth of the major human respiratory pathogen Streptococcus pneumoniae. Perturbations in Mn homeostasis genes, psaBCA, encoding the Mn importer, and mntE, encoding the Mn exporter, lead to Mn sensitivity during aerobiosis. Mn-stressed cells accumulate iron and copper, in addition to Mn. Impaired growth is a direct result of Mn toxicity and does not result from iron-mediated Fenton chemistry, since cells remain sensitive to Mn during anaerobiosis or when hydrogen peroxide biogenesis is significantly reduced. Mn-stressed cells are significantly elongated, whereas Mn-limitation imposed by zinc addition leads to cell shortening. We show that Mn accumulation promotes aberrant dephosphorylation of cell division proteins via hyperactivation of the Mn-dependent protein phosphatase PhpP, a key enzyme involved in the regulation of cell division. We discuss a mechanism by which cellular Mn:Zn ratios dictate PhpP specific activity thereby regulating pneumococcal cell division. We propose that Mn-metalloenzymes are particularly susceptible to hyperactivation or mismetallation, suggesting the need for exquisite cellular control of Mn-dependent metabolic processes.
锰（Mn）是细菌中一种必需的微量营养素和所需的辅助因子。尽管其很重要，但过量的锰会损害细菌生长，其机制在很大程度上仍未被探索。在此，我们表明适当的锰稳态对于主要人类呼吸道病原体肺炎链球菌的细胞生长至关重要。编码锰导入蛋白的锰稳态基因psaBCA和编码锰输出蛋白的mntE发生扰动，会导致需氧条件下对锰敏感。除了锰之外，受锰胁迫的细胞还会积累铁和铜。生长受损是锰毒性的直接结果，而非铁介导的芬顿化学反应导致，因为细胞在厌氧条件下或过氧化氢生物合成显著减少时仍对锰敏感。受锰胁迫的细胞明显伸长，而添加锌导致的锰限制则会使细胞缩短。我们表明，锰的积累通过锰依赖性蛋白磷酸酶PhpP的过度激活促进细胞分裂蛋白的异常去磷酸化，PhpP是参与细胞分裂调节的关键酶。我们讨论了一种机制，即细胞内锰与锌的比例决定PhpP的比活性，从而调节肺炎链球菌的细胞分裂。我们提出，锰金属酶特别容易受到过度激活或金属错配的影响，这表明需要对依赖锰的代谢过程进行精确的细胞控制。
