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.