Chapter 6 : Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm

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This chapter covers the role of iron regulation in the virulence of gram-negative bacterial pathogens, where possible, using as a paradigm. In most gram-negative bacteria, including , the alterations in mRNA and protein levels in response to iron availability are due to inherent iron requirements and iron homeostasis mechanisms controlled by two primary regulatory systems: the iron (Fe) uptake regulation protein Fur and the small RNA (sRNA) RyhB or its analogs (e.g., PrrF and NrrF). The chapter focuses on these two regulators, their regulons, and their roles in virulence. While Fur and RyhB regulons are often described separately, they are in fact interrelated regulatory networks. In a variation on the mRNA degradation theme for sodB, RyhB selectively promotes degradation of only the 3' portion of the iscRSUA mRNA, while preserving expression of IscR, a transcription factor encoded by the first gene of the operon. The chapter then focuses on the iron transport systems of . A section on RyhB regulatory mechanisms explains that RyhB regulation increases the pools of both shikimate and serine, while indirectly contributing to expression of the enterobactin biosynthesis genes. The mechanisms of Fur activation, Mn-Fur regulation, and apo-Fur regulation as well as the different regulatory mechanisms of RyhB are addressed. However, the complexity of iron regulation mechanisms and their role in microbial pathogenesis will likely provide interesting questions to resolve for decades to come.

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Figure 1

Model of Fe-Fur transcriptional repression and Fur box motifs. (A) Fur boxes for Fe-Fur binding generally overlap the −10 region of regulated promoters. During iron limitation, cytoplasmic Fe levels are sufficiently low so that Fur is primarily in its apo form. apo-Fur dimers have a lower affinity for binding to the Fur box, allowing RNA polymerase access, and transcription proceeds. Under iron surplus conditions, Fe in the bacterial cytoplasm is bound by Fur. Fe-Fur dimers bind to Fur boxes, preventing access of RNA polymerase to the promoter region, thereby preventing transcription. (B) Three alternative interpretations of Fur box motifs are shown. Arrows indicate the direct or indirect repeated sequences. The Lavrrar et al. 2002 model and data provided from the crystallographic structure of FurPa support a model in which two Fur dimmers bind on opposite sides of the DNA helix of a single Fur box, in a Fur-dependent promoter, as shown in panel A ( ). This view is also supported by the consistent observation that Fur from and protects no less than 27 to 30 bp in DNase I assays ( ). doi:10.1128/9781555818524.ch6f1

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Figure 2

Alignment of Fur amino acid sequences from (Ec), (Yp), (Vc), and P. aeruginosa (Pa). The four sequences were aligned using ClustalW2 ( ) and the EMBL-EBI website. α-Helical regions (bold, purple text and [α] labels) and β-strands (bold, green text and [β] labels) are shown for Fur based on X-ray data ( ). A consensus sequence (Con) based on these four sequences is shown. Asterisks indicate identical residues, while colons and periods indicate conservative and semiconservative changes, respectively. Residues involved in Zn binding at the Zn1 structural binding site (underlined, bold, blue text) are shown for all Fur proteins except Fur. Residues for the regulatory site for Fe binding (site 2) are shown as underlined, bold, red text for Fur and Fur. While these residues are conserved in Fur, four different Cys residues (also in underlined, bold, blue text) have been implicated in Zn binding and dimerization. However, Fur has only a single Cys residue, which functions only in dimerization. Zn1, site 1, and the Cys residues are conserved in Fur although no structure/function analyses have been performed on the protein. doi:10.1128/9781555818524.ch6f2

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Figure 3

Genetic organization of the fur locus. Designated arrows represent , , and (upstream of ) genes and show their direction of transcription. Smaller arrows indicate promoters. Transcriptional regulators CRP, Fur, OxyR, and SoxS are shown “bound” to their binding sites (similarly colored figures on the double DNA strand) within promoter regions. Indirect regulation of translation by RyhB through translation of is not shown here (see Fig. 6C ). The three alternative mRNAs are shown. Genes, transcriptional regulators, and promoter elements are not drawn to scale. doi:10.1128/9781555818524.ch6f3

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Figure 4

Model of direct transcriptional activation of by Fur. During iron limitation (A), transcription is repressed since apo-Fur does not bind to the five upstream Fur boxes. This allows H-NS to bind at these sites and other sites in the promoter region. Interaction among H-NS proteins bends the DNA, preventing access of RNA polymerase to the promoter region. Under iron surplus conditions (B), Fe-Fur binds to the upstream Fur boxes, preventing H-NS binding and interaction. This prevents occlusion of the promoter region, allowing RNA polymerase to bind and initiate transcription. doi:10.1128/9781555818524.ch6f4

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Figure 5

Model of indirect regulation of by Fur through RyhB. RyhB is expressed under low-iron conditions (A) because apo-Fur has a low affinity for binding to the Fur box in the promoter and consequently does not repress transcription. RyhB sRNA base-pairs with mRNA, causing downregulation of translation in an Hfq- and RNase E-dependent manner. Under iron-replete conditions (B), Fe-Fur binds to the promoter and prevents its transcription. SodB is expressed in the absence of RyhB-mediated repression. doi:10.1128/9781555818524.ch6f5

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Figure 6

Models showing various RyhB regulatory mechanisms. (A) RyhB sRNA base-pairs with a region of the mRNA that contains translation initiation signals (green arrow), blocking ribosome access (light blue oblongs). Hfq (purple octagon) binds both RyhB and RNase E (scissors), promoting cleavage of the mRNA by the RNA degradosome (not shown). (B) RyhB base-pairing with the cysE mRNA reduces, but does not eliminate, ribosome binding and translational readthrough to produce low levels of CysE protein (red pentagon). (C) RyhB base-pairing with the open reading frame upstream of in some organisms prevents translational readthrough into , indirectly downregulating translation. (D) RyhB's interaction with the mRNA is similar to that of mRNA, except that it base-pairs with a sequence at the start of an internal cistron rather than the 5′ end. A strong hairpin structure upstream of this binding prevents the first cistron from degradation, leaving only the portion of the mRNA intact. Blue pentagons represent IscR protein that is translated from this truncated message. (E) RyhB base-pairing with mRNA alters the mRNA folding to make the translational start site available for ribosome binding, increasing translation of . Blue pentagons represent ShiA protein. doi:10.1128/9781555818524.ch6f6

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6
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Table 1

Iron transport systems of

Citation: Perry R, McDonough K. 2013. Iron Regulation and Virulence in Gram-Negative Bacterial Pathogens with as a Paradigm, p 106-132. In Vasil M, Darwin A (ed), Regulation of Bacterial Virulence. ASM Press, Washington, DC. doi: 10.1128/9781555818524.ch6

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