Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria

Abstract

In the ancient anaerobic environment, ferrous iron (Fe2+) was one of the first metal cofactors. Oxygenation of the ancient world challenged bacteria to acquire the insoluble ferric iron (Fe3+) and later to defend against reactive oxygen species (ROS) generated by the Fenton chemistry. To acquire Fe3+, bacteria produce low-molecular weight compounds, known as siderophores, which have extremely high affinity for Fe3+. However, during infection the host restricts iron from pathogens by producing iron- and siderophore-chelating proteins, by exporting iron from intracellular pathogen-containing compartments, and by limiting absorption of dietary iron. Ferric Uptake Regulator (Fur) is a transcription factor which utilizes Fe2+ as a corepressor and represses siderophore synthesis in pathogens. Fur, directly or indirectly, controls expression of enzymes that protect against ROS damage. Thus, the challenges of iron homeostasis and defense against ROS are addressed via Fur. Although the role of Fur as a repressor is well-documented, emerging evidence demonstrates that Fur can function as an activator. Fur activation can occur through three distinct mechanisms (1) indirectly via small RNAs, (2) binding at cis regulatory elements that enhance recruitment of the RNA polymerase holoenzyme (RNAP), and (3) functioning as an antirepressor by removing or blocking DNA binding of a repressor of transcription. In addition, Fur homologs control defense against peroxide stress (PerR) and control uptake of other metals such as zinc (Zur) and manganese (Mur) in pathogenic bacteria. Fur family members are important for virulence within bacterial pathogens since mutants of fur, perR, or zur exhibit reduced virulence within numerous animal and plant models of infection. This review focuses on the breadth of Fur regulation in pathogenic bacteria.

Functional genomics of Lactobacillus casei establishment in the gut

“…In most pathogens Fur proteins act as central regulators for successful colonization and virulence. They control genes involved in iron homeostasis and protection against reactive oxygen species damage (62) in Shigella (63), Salmonella (64), Vibrio cholerae (65), Pseudomonas (66), Listeria (67), and Helicobacter pylori (68). Therefore it is likely that L. casei is strongly challenged by iron-limiting conditions in the gut, particularly given the high levels of lactoferrin in intestinal secretions.…”

The Small RNA RyhB Contributes to Siderophore Production and Virulence of Uropathogenic Escherichia coli

“…When iron availability is limited, Fur becomes inactive, and subsequently, the production of RyhB and iron acquisition systems is initiated in order to restore iron homeostasis (1,4,(8)(9)(10). In addition, Fur regulates several genes involved in other cellular processes, such as metabolic pathways, acid tolerance, virulence factor production, and protection against oxidative stress, in many pathogens, including E. coli, Pseudomonas aeruginosa, Vibrio cholerae, and Salmonella enterica (11)(12)(13)(14)(15)(16).…”

Metal economy in host-microbe interactions

“…Porcheron et al (2013) review the enterobacterial metallo-transporters and their regulation, discussing strain-specific differences. Troxell and Hassan (2013) review Fe-dependent regulations of transcription by the Ferric Uptake Regulator to control iron metabolism, oxidative stress defense and virulence. Finally, Troxell and Yang (2013) present the metallo-regulation in the causative agent of Lyme disease (Borrelia burgdorferi) a bacterium that does not require iron for its metabolism.…”