Salmonella Facilitates Iron Acquisition through UMPylation of Ferric Uptake Regulator

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 ΔydiU strain than in wild-type Salmonella, and the ΔydiU strain exhibited severe growth defect under metal deficiency environments. Genome-wide expression analyses revealed significantly decreased expression of iron uptake genes in ΔydiU 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 in vivo and in vitro. 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. IMPORTANCE 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.