Fe–S clusters, fragile sentinels of the cell

Py, Béatrice; Moreau, P.; Barras, Frédéric

doi:10.1016/j.mib.2011.01.004

Cited by 68 publications

(58 citation statements)

References 55 publications

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“…Iron starvation and oxidative stress, frequently encountered by most bacterial pathogens upon infection (40,41), are two conditions that are highly detrimental for maintaining Fe-S cluster homeostasis (9)(10)(11)(12)42). Accordingly, Fe-S cluster biogenesis and its regulation are crucial for the pathogenesis of Erwinia chrysanthemi and Shigella flexneri, allowing adaptation to hostile host environments (43,44).…”

Section: Discussionmentioning

confidence: 99%

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

Lim

Choi

2014

Infect Immun

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A mutant that exhibited less cytotoxic activity toward INT-407 human intestinal epithelial cells than the wild type was screened from a random transposon mutant library of Vibrio vulnificus, and an open reading frame encoding an Fe-S cluster regulator, IscR, was identified using a transposon-tagging method. A mutational analysis demonstrated that IscR contributes to mouse mortality as well as cytotoxicity toward the INT-407 cells, indicating that IscR is essential for the pathogenesis of V. vulnificus. A whole-genome microarray analysis revealed that IscR influenced the expression of 67 genes, of which 52 were upregulated and 15 were downregulated. Among these, 12 genes most likely involved in motility and adhesion to host cells, hemolytic activity, and survival under oxidative stress of the pathogen during infection were selected and experimentally verified to be upregulated by IscR. Accordingly, the disruption of iscR resulted in a significant reduction in motility and adhesion to INT-407 cells, in hemolytic activity, and in resistance to reactive oxygen species (ROS) such as H 2 O 2 and tert-butyl hydroperoxide (t-BOOH). Furthermore, the present study demonstrated that iscR expression was induced by exposure of V. vulnificus to the INT-407 cells, and the induction appeared to be mediated by ROS generated by the host cells during infection. Consequently, the combined results indicated that IscR is a global regulator that contributes to the overall success in the pathogenesis of V. vulnificus by regulating the expression of various virulence and survival genes in addition to Fe-S cluster genes. Most of virulence factors of pathogenic bacteria act cooperatively to obtain maximum effectiveness during pathogenesis while their expression is coordinately regulated by common global regulators in response to environmental conditions, and this coordinated regulation facilitates the cooperation of virulence factors and is crucial to the overall success of the pathogens during infection (1, 2). Vibrio vulnificus is an opportunistic Gram-negative pathogen that frequently contaminates oysters. It has been proposed that numerous virulence factors account for the fulminating and destructive nature of V. vulnificus infections and contribute to not only disease development but also the survival and multiplication on or within the host (for a recent review, see reference 3). However, studies about global regulators involved in the regulation of V. vulnificus virulence factors are still very limited.Iron-sulfur proteins containing the Fe-S cluster as a cofactor carry out multiple important cellular processes such as electron transfer, metabolic reactions, and gene regulation and are widely distributed (for recent reviews, see references 4 and 5). A highly conserved isc operon, iscRSUA-hscBA-fdx, was discovered to encode all of the proteins required for the biogenesis of the majority, if not all, of the Fe-S cluster proteins in Escherichia coli (for recent reviews, see references 5 and 6). Expression of the isc operon is autoregu...

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Section: Discussionmentioning

confidence: 99%

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

Lim

Choi

2014

Infect Immun

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“…Salmonella contains two Fe-S cluster biosynthetic systems, Isc and Suf (92); transcriptional upregulation of genes involved in both systems was seen in early lag phase within 4 to 20 min (Fig. 4H).…”

Section: Rna Polymerase Is Not Poised At Lag-inducible Promotersmentioning

confidence: 99%

Lag Phase Is a Distinct Growth Phase That Prepares Bacteria for Exponential Growth and Involves Transient Metal Accumulation

et al. 2012

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Lag phase represents the earliest and most poorly understood stage of the bacterial growth cycle. We developed a reproducible experimental system and conducted functional genomic and physiological analyses of a 2-h lag phase in Salmonella enterica serovar Typhimurium. Adaptation began within 4 min of inoculation into fresh LB medium with the transient expression of genes involved in phosphate uptake. The main lag-phase transcriptional program initiated at 20 min with the upregulation of 945 genes encoding processes such as transcription, translation, iron-sulfur protein assembly, nucleotide metabolism, LPS biosynthesis, and aerobic respiration. ChIP-chip revealed that RNA polymerase was not "poised" upstream of the bacterial genes that are rapidly induced at the beginning of lag phase, suggesting a mechanism that involves de novo partitioning of RNA polymerase to transcribe 522 bacterial genes within 4 min of leaving stationary phase. We used inductively coupled plasma mass spectrometry (ICP-MS) to discover that iron, calcium, and manganese are accumulated by S. Typhimurium during lag phase, while levels of cobalt, nickel, and sodium showed distinct growth-phase-specific patterns. The high concentration of iron during lag phase was associated with transient sensitivity to oxidative stress. The study of lag phase promises to identify the physiological and regulatory processes responsible for adaptation to new environments.

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“…Given their significant roles, a major objective has been to understand how Fe-S clusters are assembled and how cellular Fe-S cluster homeostasis is maintained in response to environmental cues, such as O 2 or reactive oxygen species (ROS), which can destabilize Fe-S clusters (4)(5)(6). In Escherichia coli, the majority of Fe-S cluster biogenesis is catalyzed by proteins of the housekeeping Isc pathway, encoded by the iscRSUA-hscBA-fdx (isc) operon (7)(8)(9). The isc operon also encodes IscR, a [2Fe-2S] transcription factor that modulates expression of the Isc pathway according to the cellular needs for Fe-S cluster biogenesis.…”

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confidence: 99%

“…Indeed, deletion of suf was previously shown to have no effect on [2Fe-2S]-IscR activity under nonstress conditions (10). Nevertheless, the Suf pathway includes proteins that exhibit functional similarity to those of the Isc pathway (8,9). For example, the cysteine desulfurases IscS and SufSE provide sulfur to the respective scaffold proteins, IscU and SufB, upon which Fe-S clusters are transiently assembled.…”

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confidence: 99%

Coordinate Regulation of the Suf and Isc Fe-S Cluster Biogenesis Pathways by IscR Is Essential for Viability of Escherichia coli

Mettert

Kiley

2014

J Bacteriol

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Fe-S cluster biogenesis is essential for the viability of most organisms. In Escherichia coli, this process requires either the housekeeping Isc or the stress-induced Suf pathway. The global regulator IscR coordinates cluster synthesis by repressing transcription of the isc operon by [2Fe-2S]-IscR and activating expression of the suf operon. We show that either [2Fe-2S]-IscR or apoIscR can activate suf, making expression sensitive to mainly IscR levels and not the cluster state, unlike isc expression. We also demonstrate that in the absence of isc, IscR-dependent suf activation is essential since strains lacking both the Isc pathway and IscR were not viable unless Suf was expressed ectopically. Similarly, removal of the IscR binding site in the sufA promoter also led to a requirement for isc. Furthermore, suf expression was increased in a ⌬isc mutant, presumably due to increased IscR levels in this mutant. This was surprising because the iron-dependent repressor Fur, whose higher-affinity binding at the sufA promoter should occlude IscR binding, showed only partial repression. In addition, Fur derepression was not sufficient for viability in the absence of IscR and the Isc pathway, highlighting the importance of direct IscR activation. Finally, a mutant lacking Fur and the Isc pathway increased suf expression to the highest observed levels and nearly restored [2Fe-2S]-IscR activity, providing a mechanism for regulating IscR activity under stress conditions. Together, these findings have enhanced our understanding of the homeostatic mechanism by which cells use one regulator, IscR, to differentially control Fe-S cluster biogenesis pathways to ensure viability.

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Fe–S clusters, fragile sentinels of the cell

Cited by 68 publications

References 55 publications

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

IscR Is a Global Regulator Essential for Pathogenesis of Vibrio vulnificus and Induced by Host Cells

Lag Phase Is a Distinct Growth Phase That Prepares Bacteria for Exponential Growth and Involves Transient Metal Accumulation

Coordinate Regulation of the Suf and Isc Fe-S Cluster Biogenesis Pathways by IscR Is Essential for Viability of Escherichia coli

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