Abstract
Aerobactin is a citrate-hydroxamate siderophore that is critical for the virulence of pathogenic enteric bacteria. However, although the aerobactin-producing iucABCD-iutA operon is distributed widely in the genomes of Yersinia species, none of the pathogenic Yersinia spp. was found to produce aerobactin. Here, we showed that the iucABCD-iutA operon in the food-borne enteric pathogen Yersinia pseudotuberculosis YPIII is a functional siderophore system involved in iron acquisition. The expression of the operon was found to be directly repressed by the ferric uptake regulator (Fur) in an iron concentration-dependent manner. In addition, we demonstrated that the aerobactin-mediated iron acquisition contributes to bacterial growth under iron-limited conditions. Moreover, we provided evidence that aerobactin plays important roles in biofilm formation, resistance to oxidative stress, ROS removal, and virulence of Y. pseudotuberculosis. Overall, our study not only uncovered a novel strategy of iron acquisition in Y. pseudotuberculosis but also highlighted the importance of aerobactin in the pathogenesis of Y. pseudotuberculosis.
Highlights
Iron is an irreplaceable metal for most of living organisms, as it is necessary for the activity of functional proteins or regulators that are involved in many cellular processes such as the tricarboxylic acid (TCA) cycle, DNA precursor synthesis, and oxygen metabolism (Neilands, 1981; Galaris and Pantopoulos, 2008)
Genome analysis of Y. pseudotuberculosis YPIII identified a putative aerobactin-producing iucABCD-iutA operon, which is similar to the functional characterized iucABCD-iutA operon in Escherichia coli, Shigella flexneri, Vibrio mimicus, and Klebsiella pneumoniae in the operon structure (Figure 1A; Payne, 1980; Nassif and Sansonetti, 1986; Okujo and Yamamoto, 1994; Peigne et al, 2009). In this Y. pseudotuberculosis iucABCDiutA operon, the first gene iucA encodes a IucA ortholog with 63% identity to an E. coli IucA that is implicated in couple ahLys onto the primary carboxylates of citrate to synthesize aerobactin siderophore (Figure 1A; Neilands, 1992; Marchler-Bauer et al, 2013)
Previous studies reported that Y. pestis and Y. pseudotuberculosis are incapable of producing aerobactin even though they possess the iucABCD-iutA operon (Forman et al, 2007)
Summary
Iron is an irreplaceable metal for most of living organisms, as it is necessary for the activity of functional proteins or regulators that are involved in many cellular processes such as the tricarboxylic acid (TCA) cycle, DNA precursor synthesis, and oxygen metabolism (Neilands, 1981; Galaris and Pantopoulos, 2008). Siderophores are low-molecular-weight (500–1,500 Da) high-affinity iron-chelating compounds for solubilization and transport of ferric iron into bacterial cells (Neilands, 1995). In the extracellular milieu, secreted siderophores form soluble iron–siderophore complexes with ferric iron. The soluble iron– siderophore complexes are actively transported into bacterial cells via specific outer membrane receptors, ferric iron is released and reduced to ferrous iron, which can be used for cellular needs (Chakraborty et al, 2007). Ferric uptake regulator (Fur) is the key regulator, which acts as a transcriptional repressor of siderophore synthesis genes by utilizing ferrous iron as a corepressor (Ratledge and Dover, 2000; Miethke and Marahiel, 2007). In iron-rich environments, the ferrous iron-Fur dimer binds to the promoter regions of siderophore synthesis genes to block transcription. Fur no longer contains ferrous iron; it is detached from the siderophore gene promoter to relieve repression and the eventual synthesis of siderophores (Troxell and Hassan, 2013)
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