Pathogenic bacteria employ complex systems to cope with metal ion shortage conditions and propagate in the host. IsrR is a regulatory RNA (sRNA) whose activity is decisive for optimum Staphylococcus aureus fitness upon iron starvation and for full virulence. IsrR down-regulates several genes encoding iron-containing enzymes to spare iron for essential processes. Here, we report that IsrR regulates the tricarboxylic acid (TCA) cycle by controlling aconitase (CitB), an iron-sulfur cluster-containing enzyme, and its transcriptional regulator, CcpE. This IsrR-dependent dual-regulatory mechanism provides an RNA-driven feedforward loop, underscoring the tight control required to prevent aconitase expression. Beyond its canonical enzymatic role, aconitase becomes an RNA-binding protein with regulatory activity in iron-deprived conditions, a feature that is conserved in S. aureus. Aconitase not only negatively regulates its own expression, but also impacts the enzymes involved in both its substrate supply and product utilization. This moonlighting activity concurrently upregulates pyruvate carboxylase expression, allowing it to compensate for the TCA cycle deficiency associated with iron scarcity. These results highlight the cascade of complex posttranscriptional regulations controlling S. aureus central metabolism in response to iron deficiency.

中文翻译：

---

缺铁期间葡萄球菌乌头酸酶的表达由 sRNA 驱动的前馈环和兼职活动控制


致病细菌利用复杂的系统来应对金属离子缺乏条件并在宿主中繁殖。 IsrR 是一种调节性 RNA (sRNA)，其活性对于金黄色葡萄球菌在铁饥饿时的最佳适应性和完全毒力具有决定性作用。 IsrR 下调多个编码含铁酶的基因，从而为重要过程保留铁。在此，我们报道 IsrR 通过控制乌头酸酶 (CitB)（一种含有铁硫簇的酶）及其转录调节因子 CcpE 来调节三羧酸 (TCA) 循环。这种 IsrR 依赖性双调节机制提供了 RNA 驱动的前馈环，强调了防止乌头酸酶表达所需的严格控制。除了其典型的酶作用外，乌头酸酶还成为一种 RNA 结合蛋白，在缺铁条件下具有调节活性，这是金黄色葡萄球菌中保守的特征。乌头酸酶不仅负面调节其自身的表达，而且影响参与其底物供应和产物利用的酶。这种兼职活动同时上调丙酮酸羧化酶的表达，使其能够补偿与铁缺乏相关的 TCA 循环缺陷。这些结果强调了控制金黄色葡萄球菌中枢代谢以应对缺铁的复杂转录后调控的级联反应。