Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Department of Pathogen Biology, School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
mBio. 2022 Jun 28;13(3):e0020722. doi: 10.1128/mbio.00207-22. Epub 2022 May 9.
Iron limitation is a universal strategy of host immunity during bacterial infection. However, the mechanisms by which pathogens antagonize host nutritional immunity have not been fully elucidated. Here, we identified a requirement for the UMPylator YdiU for this process in Salmonella. The expression of YdiU was dramatically induced by the metal starvation signal. The intracellular iron content was much lower in the Δ strain than in wild-type Salmonella, and the Δ strain exhibited severe growth defect under metal deficiency environments. Genome-wide expression analyses revealed significantly decreased expression of iron uptake genes in Δ strain compared with the wild-type strain. Interestingly, YdiU did not affect the expression level of the major iron uptake regulator Fur but directly UMPylated Fur on its H118 residue and . UMPylation destroyed the Fur dimer, promoted Fur aggregation, and eliminated the DNA-binding activity of Fur, thus abolishing the ability of Fur to inhibit iron uptake. Restricting Fur to the deUMPylated state dramatically eliminates Salmonella iron uptake in iron deficiency environments. In parallel, YdiU facilitates Salmonella survival within host cells by regulating the iron uptake pathway. Salmonella is the major pathogen causing bacterial enteric illness in both humans and animals. Iron availability is strictly controlled upon Salmonella entry into host cells. The mechanisms by which Salmonella balances the acquisition of sufficient iron while preventing a toxic overload has not been fully understood. Here, we reveal a novel regulation process of iron acquisition mediated by the UMPylator YdiU. Fur acts as the central regulator of bacterial iron homeostasis. YdiU UMPylates Fur on H118 and prevents Fur from binding to target DNA, thus activating the expression of iron uptake genes under iron-deficient conditions. We describe the first posttranslational modification-based regulation of Fur and highlight a potential mechanism by which Salmonella can adapt to eliminate host nutritional immunity.
铁限制是宿主在细菌感染期间免疫的一种普遍策略。然而，病原体拮抗宿主营养免疫的机制尚未完全阐明。在这里，我们确定了 UMPylator YdiU 在沙门氏菌中对此过程的需求。金属饥饿信号可显著诱导 YdiU 的表达。Δ 株的细胞内铁含量明显低于野生型沙门氏菌，并且在金属缺乏环境下，Δ 株表现出严重的生长缺陷。全基因组表达分析显示，与野生型菌株相比，Δ 株中铁摄取基因的表达水平显著降低。有趣的是，YdiU 不影响主要铁摄取调节剂 Fur 的表达水平，但直接在其 H118 残基和 上 UMPylate Fur。UMPylation 破坏了 Fur 二聚体，促进了 Fur 的聚集，并消除了 Fur 的 DNA 结合活性，从而消除了 Fur 抑制铁摄取的能力。将 Fur 限制在去 UMPylated 状态可显著消除铁缺乏环境中沙门氏菌的铁摄取。与此同时，YdiU 通过调节铁摄取途径促进沙门氏菌在宿主细胞内的存活。沙门氏菌是导致人类和动物细菌性肠道疾病的主要病原体。铁的可用性在沙门氏菌进入宿主细胞时受到严格控制。沙门氏菌如何平衡获取足够的铁同时防止毒性过载的机制尚未完全理解。在这里，我们揭示了一种由 UMPylator YdiU 介导的铁摄取的新调控过程。Fur 是细菌铁稳态的中心调节剂。YdiU 在 H118 上 UMPylate Fur，防止 Fur 与靶 DNA 结合，从而在缺铁条件下激活铁摄取基因的表达。我们描述了 Fur 的第一个基于翻译后修饰的调控，并强调了沙门氏菌适应消除宿主营养免疫的潜在机制。
