Abstract
The ferric uptake regulator (Fur) plays a major role in controlling the expression of iron homeostasis genes in bacterial organisms. In this work, we fully characterized the capacity of Fur to reconfigure the global transcriptional network and influence iron homeostasis in Enterococcus faecalis. The characterization of the Fur regulon from E. faecalis indicated that this protein (Fur) regulated the expression of genes involved in iron uptake systems, conferring to the system a high level of efficiency and specificity to respond under different iron exposure conditions. An RNAseq assay coupled with a systems biology approach allowed us to identify the first global transcriptional network activated by different iron treatments (excess and limited), with and without the presence of Fur. The results showed that changes in iron availability activated a complex network of transcriptional factors in E. faecalis, among them global regulators such as LysR, ArgR, GalRS, and local regulators, LexA and CopY, which were also stimulated by copper and zinc treatments. The deletion of Fur impacted the expression of genes encoding for ABC transporters, energy production and [Fe-S] proteins, which optimized detoxification and iron uptake under iron excess and limitation, respectively. Finally, considering the close relationship between iron homeostasis and pathogenesis, our data showed that the absence of Fur increased the internal concentration of iron in the bacterium and also affected its ability to produce biofilm. These results open new alternatives in the field of infection mechanisms of E. faecalis.
Highlights
Iron is an essential metal required for several bacterial species (Chandrangsu et al, 2017)
In order to in silico validate the predicted gene annotation, we modeled ferric uptake regulator (Fur) of E. faecalis using the closed conformation of Fur from Vibrio cholerae
In order to determine the influence of Fur over iron homeostasis in E. faecalis, we evaluated if the absence of the Fur impacted the viability of the bacterium growing under different scenarios of iron exposure
Summary
Iron is an essential metal required for several bacterial species (Chandrangsu et al, 2017). The mechanisms of action of this regulator are highly conserved in multiple bacterial pathogens (Carpenter et al, 2009; Lee et al, 2014; Ludwig et al, 2015; Pelliciari et al, 2015), including Helicobacter pylori, Vibrio sp., Pseudomonas sp., Shigella flexneri, and Bacillus subtilis This transcriptional factor represses its target genes when the intracellular concentration of iron exceeds threshold levels (Fuangthong and Helmann, 2003). Besides its participation in iron metabolism, Fur contributes to pathogenesis, acting as a positive regulator of genes that encode virulence factors and proteins with roles in oxidative and pH-mediated stress responses, supporting the importance of Fur in the transcriptional regulation of several metabolic processes (Foster, 1991; Troxell and Hassan, 2013; Porcheron and Dozois, 2015). Using a systems biology approach, we determined the relevance of Fur over the global transcriptional response of E. faecalis under iron deficiency and excess conditions, showing that this bacterium has the capacity to reconfigure its gene network, activating others transcriptional regulators in order to maintain iron homeostasis
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