Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Bacteriol. 2024 Apr 18;206(4):e0003124. doi: 10.1128/jb.00031-24. Epub 2024 Mar 27.
A hallmark of infection of the urinary tract is the formation of stones. The ability to induce urinary stone formation requires urease, a nickel metalloenzyme that hydrolyzes urea. This reaction produces ammonia as a byproduct, which can serve as a nitrogen source and weak base that raises the local pH. The resulting alkalinity induces the precipitation of ions to form stones. Transcriptional regulator UreR activates expression of urease genes in a urea-dependent manner. Thus, urease genes are highly expressed in the urinary tract where urea is abundant. Production of mature urease also requires the import of nickel into the cytoplasm and its incorporation into the urease apoenzyme. Urease accessory proteins primarily acquire nickel from one of two nickel transporters and facilitate incorporation of nickel to form mature urease. In this study, we performed a comprehensive RNA-seq to define the urea-induced transcriptome as well as the UreR regulon. We identified UreR as the first defined regulator of nickel transport in . We also offer evidence for the direct regulation of the Ynt nickel transporter by UreR. Using bioinformatics, we identified UreR-regulated urease loci in 15 family species across three genera. Additionally, we located two mobilized UreR-regulated urease loci that also encode the transporter, implying that UreR regulation of nickel transport is a conserved regulatory relationship. Our study demonstrates that UreR specifically regulates genes required to produce mature urease, an essential virulence factor for uropathogenesis.
Catheter-associated urinary tract infections (CAUTIs) account for over 40% of acute nosocomial infections in the USA and generate $340 million in healthcare costs annually. A major causative agent of CAUTIs is , an understudied Gram-negative pathogen noted for its ability to form urinary stones via the activity of urease. Urease mutants cannot induce stones and are attenuated in a murine UTI model, indicating this enzyme is essential to pathogenesis. Transcriptional regulation of urease genes by UreR is well established; here, we expand the UreR regulon to include regulation of nickel import, a function required to produce mature urease. Furthermore, we reflect on the role of urea catalysis in metabolism and provide evidence for its importance.
尿路感染的一个标志是结石的形成。形成结石的能力需要脲酶，这是一种镍金属酶，可水解尿素。该反应产生的氨作为副产物，可以作为氮源和弱碱，提高局部 pH 值。由此产生的碱性诱导离子沉淀形成结石。转录调节因子 UreR 以尿素依赖的方式激活脲酶基因的表达。因此，在富含尿素的尿路中，脲酶基因高度表达。成熟脲酶的产生还需要将镍导入细胞质并将其掺入脲酶脱辅基中。脲酶辅助蛋白主要从两种镍转运蛋白之一获得镍，并促进镍的掺入以形成成熟的脲酶。在这项研究中，我们进行了全面的 RNA-seq 以定义尿素诱导的转录组和 UreR 调控组。我们确定 UreR 是 中镍转运的第一个定义调节剂。我们还提供了 UreR 直接调节 Ynt 镍转运蛋白的证据。通过生物信息学，我们在三个属的 15 种 家族物种中鉴定出 UreR 调节的脲酶基因座。此外，我们定位了两个可移动的 UreR 调节的脲酶基因座，也编码转运蛋白，这意味着 UreR 对镍转运的调节是一种保守的调节关系。我们的研究表明，UreR 特异性调节产生成熟脲酶所需的基因，而成熟脲酶是 尿路致病性的必需毒力因子。
在美国，导管相关尿路感染 (CAUTI) 占急性医院获得性感染的 40%以上，每年产生 3.4 亿美元的医疗保健费用。CAUTI 的主要病原体之一是 ，这是一种研究不足的革兰氏阴性病原体，其特点是通过脲酶的活性形成尿路感染结石。脲酶突变体不能诱导结石，并且在小鼠尿路感染模型中减弱，表明该酶对 发病机制至关重要。UreR 对脲酶基因的转录调控已得到很好的证实；在这里，我们将 UreR 调控组扩展到包括镍导入的调控，这是产生成熟脲酶所必需的功能。此外，我们反思了尿素催化在 代谢中的作用，并提供了其重要性的证据。
