Ethylene is involved in the regulation of iron homeostasis by regulating the expression of iron-acquisition-related genes in Oryza sativa

Cystic fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations. It is a multiorgan system disease that affects the lungs, gastrointestinal tract, liver, and pancreas. The majority of morbidity and mortality in CF relates to chronic airway infection with a variety of bacterial species, commencing in very early infancy, which results in lung destruction and ultimately organ failure ( 41 , 43 ). This review focuses on iron homeostasis in the CF lung and its role in determining the success and chronicity of Pseudomonas aeruginosa infection. There have been previous excellent reviews regarding iron metabolism in the lower respiratory tract and mechanisms of P. aeruginosa iron acquisition, and we direct readers to these articles for further background reading ( 31 , 53 , 58 , 77 , 96 ). In this review, we have brought the “two sides of the coin” together to provide a holistic overview of the relationship between host and bacterial iron homeostasis and put this information into the context of current understanding on infection in the CF lung.

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Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽

10.1128/mbio.02624-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Stefanie Dichtl ◽

Egon Demetz ◽

David Haschka ◽

Piotr Tymoszuk ◽

Verena Petzer ◽

...

Keyword(s):

Bacterial Growth ◽

Iron Uptake ◽

Iron Homeostasis ◽

Iron Acquisition ◽

Lipocalin 2 ◽

Intracellular Iron ◽

Content Type ◽

Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

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The Role of SreA-Mediated Iron Regulation in Maintaining Epichloë festucae–Lolium perenne Symbioses

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-03-19-0060-r ◽

2019 ◽

Vol 32 (10) ◽

pp. 1324-1335 ◽

Cited By ~ 3

Author(s):

Natasha T. Forester ◽

Geoffrey A. Lane ◽

Catherine M. McKenzie ◽

Iain L. Lamont ◽

Linda J. Johnson

Keyword(s):

Iron Uptake ◽

Iron Homeostasis ◽

Iron Acquisition ◽

Functional Characterization ◽

Fungal Growth ◽

Hyphal Growth ◽

Epichloë Festucae ◽

Gradual Loss ◽

Growth Assay ◽

Iron Management

In ascomycetes and basidiomycetes, iron-responsive GATA-type transcriptional repressors are involved in regulating iron homeostasis, notably to prevent iron toxicity through control of iron uptake. To date, it has been unknown whether this iron regulator contributes toward mutualistic endosymbiosis of microbes with plants, a system where the endophyte must function within the constraints of an in-host existence, including a dependency on the host for nutrient acquisition. Functional characterization of one such protein, SreA from Epichloë festucae, a fungal endosymbiont of cool-season grasses, indicates that regulation of iron homeostasis processes is important for symbiotic maintenance. The deletion of the sreA gene (ΔsreA) led to iron-dependent aberrant hyphal growth and the gradual loss of endophyte hyphae from perennial ryegrass. SreA negatively regulates the siderophore biosynthesis and high-affinity iron uptake systems of E. festucae, similar to other fungi, resulting in iron accumulation in mutants. Our evidence suggests that SreA is involved in the processes that moderate Epichloë iron acquisition from the plant apoplast, because overharvesting of iron in ΔsreA mutants was detected as premature chlorosis of the host using a hydroponic plant growth assay. E. festucae appears to have a tightly regulated iron management system, involving SreA that balances endophyte growth with its survival and prevents overcompetition with the host for iron in the intercellular niche, thus promoting mutualistic associations. Mutations that interfere with Epichloë iron management negatively affect iron-dependent fungal growth and destabilize mutualistic Epichloë –ryegrass associations.

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Hepcidin: A Critical Regulator of Iron Metabolism during Hypoxia

Advances in Hematology ◽

10.1155/2011/510304 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 22

Author(s):

Korry J. Hintze ◽

James P. McClung

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Absorption ◽

Iron Acquisition ◽

Iron Status ◽

Hypoxia Inducible Factor ◽

Hypoxia Response Element ◽

Hypoxia Response ◽

Hepcidin Expression

Iron status affects cognitive and physical performance in humans. Recent evidence indicates that iron balance is a tightly regulated process affected by a series of factors other than diet, to include hypoxia. Hypoxia has profound effects on iron absorption and results in increased iron acquisition and erythropoiesis when humans move from sea level to altitude. The effects of hypoxia on iron balance have been attributed to hepcidin, a central regulator of iron homeostasis. This paper will focus on the molecular mechanisms by which hypoxia affects hepcidin expression, to include a review of the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system, as well as recent evidence indicating that localized adipose hypoxia due to obesity may affect hepcidin signaling and organismal iron metabolism.

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Strong iron demand during hypoxia-induced erythropoiesis is associated with down-regulation of iron-related proteins and myoglobin in human skeletal muscle

Blood ◽

10.1182/blood-2006-08-040006 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4724-4731 ◽

Cited By ~ 79

Author(s):

Paul Robach ◽

Gaetano Cairo ◽

Cecilia Gelfi ◽

Francesca Bernuzzi ◽

Henriette Pilegaard ◽

...

Keyword(s):

Skeletal Muscle ◽

Iron Content ◽

Iron Homeostasis ◽

Iron Acquisition ◽

Hypoxia Inducible Factor ◽

Hemoglobin Concentration ◽

Oxygen Binding ◽

Mrna Levels ◽

Iron Regulatory Proteins ◽

Related Proteins

Abstract Iron is essential for oxygen transport because it is incorporated in the heme of the oxygen-binding proteins hemoglobin and myoglobin. An interaction between iron homeostasis and oxygen regulation is further suggested during hypoxia, in which hemoglobin and myoglobin syntheses have been reported to increase. This study gives new insights into the changes in iron content and iron-oxygen interactions during enhanced erythropoiesis by simultaneously analyzing blood and muscle samples in humans exposed to 7 to 9 days of high altitude hypoxia (HA). HA up-regulates iron acquisition by erythroid cells, mobilizes body iron, and increases hemoglobin concentration. However, contrary to our hypothesis that muscle iron proteins and myoglobin would also be up-regulated during HA, this study shows that HA lowers myoglobin expression by 35% and down-regulates iron-related proteins in skeletal muscle, as evidenced by decreases in L-ferritin (43%), transferrin receptor (TfR; 50%), and total iron content (37%). This parallel decrease in L-ferritin and TfR in HA occurs independently of increased hypoxia-inducible factor 1 (HIF-1) mRNA levels and unchanged binding activity of iron regulatory proteins, but concurrently with increased ferroportin mRNA levels, suggesting enhanced iron export. Thus, in HA, the elevated iron requirement associated with enhanced erythropoiesis presumably elicits iron mobilization and myoglobin down-modulation, suggesting an altered muscle oxygen homeostasis.

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Nitric oxide–mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection

Journal of Experimental Medicine ◽

10.1084/jem.20121946 ◽

2013 ◽

Vol 210 (5) ◽

pp. 855-873 ◽

Cited By ~ 109

Author(s):

Manfred Nairz ◽

Ulrike Schleicher ◽

Andrea Schroll ◽

Thomas Sonnweber ◽

Igor Theurl ◽

...

Keyword(s):

Nitric Oxide ◽

Iron Homeostasis ◽

Molecular Mechanisms ◽

Iron Acquisition ◽

Iron Chelator ◽

Related Factor ◽

Cellular Iron ◽

Splenic Macrophages ◽

Ferroportin 1 ◽

Pathogen Control

Nitric oxide (NO) generated by inducible NO synthase 2 (NOS2) affects cellular iron homeostasis, but the underlying molecular mechanisms and implications for NOS2-dependent pathogen control are incompletely understood. In this study, we found that NO up-regulated the expression of ferroportin-1 (Fpn1), the major cellular iron exporter, in mouse and human cells. Nos2−/− macrophages displayed increased iron content due to reduced Fpn1 expression and allowed for an enhanced iron acquisition by the intracellular bacterium Salmonella typhimurium. Nos2 gene disruption or inhibition of NOS2 activity led to an accumulation of iron in the spleen and splenic macrophages. Lack of NO formation resulted in impaired nuclear factor erythroid 2-related factor-2 (Nrf2) expression, resulting in reduced Fpn1 transcription and diminished cellular iron egress. After infection of Nos2−/− macrophages or mice with S. typhimurium, the increased iron accumulation was paralleled by a reduced cytokine (TNF, IL-12, and IFN-γ) expression and impaired pathogen control, all of which were restored upon administration of the iron chelator deferasirox or hyperexpression of Fpn1 or Nrf2. Thus, the accumulation of iron in Nos2−/− macrophages counteracts a proinflammatory host immune response, and the protective effect of NO appears to partially result from its ability to prevent iron overload in macrophages

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Iron homeostasis in tropical indica rice (Oryza sativa L.) cultivars having contrasting grain iron concentration

Journal of Plant Biochemistry and Biotechnology ◽

10.1007/s13562-016-0350-1 ◽

2016 ◽

Vol 25 (4) ◽

pp. 382-391

Author(s):

Binay Bhusan Panda ◽

Srigopal Sharma ◽

Pravat Kumar Mohapatra ◽

Avijit Das

Keyword(s):

Oryza Sativa ◽

Iron Homeostasis ◽

Oryza Sativa L ◽

Indica Rice ◽

Iron Concentration

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The Transcriptomic and Bioinformatic Characterizations of Iron Acquisition and Heme Utilization in Avibacterium paragallinarum in Response to Iron-Starvation

Frontiers in Microbiology ◽

10.3389/fmicb.2021.610196 ◽

2021 ◽

Vol 12 ◽

Author(s):

Caiyun Huo ◽

Ximin Zeng ◽

Fuzhou Xu ◽

Fangbing Li ◽

Donghai Li ◽

...

Keyword(s):

Iron Homeostasis ◽

Iron Acquisition ◽

Control Group ◽

Rna Seq ◽

Iron Starvation ◽

Transcriptomic Response ◽

Iron Restriction ◽

Infectious Coryza ◽

Avibacterium Paragallinarum ◽

Restriction Group

Avibacterium paragallinarum is the pathogen of infectious coryza, which is a highly contagious respiratory disease of chickens that brings a potentially serious threat to poultry husbandry. Iron is an important nutrient for bacteria and can be obtained from surroundings such as siderophores and hemophores. To date, the mechanisms of iron acquisition and heme utilization as well as detailed regulation in A. paragallinarum have been poorly understood. In this study, we investigated the transcriptomic profiles in detail and the changes of transcriptomes induced by iron restriction in A. paragallinarum using RNA-seq. Compared with the iron-sufficiency control group, many more differentially expressed genes (DEGs) and cellular functions as well as signaling pathways were verified in the iron-restriction group. Among these DEGs, the majority of genes showed decreased expression and some were found to be uniquely present in the iron-restriction group. With an in-depth study of bioinformatic analyses, we demonstrated the crucial roles of the Hut protein and DUF domain-containing proteins, which were preferentially activated in bacteria following iron restriction and contributed to the iron acquisition and heme utilization. Consequently, RT-qPCR results further verified the iron-related DEGs and were consistent with the RNA-seq data. In addition, several novel sRNAs were present in A. paragallinarum and had potential regulatory roles in iron homeostasis, especially in the regulation of Fic protein to ensure stable expression. This is the first report of the molecular mechanism of iron acquisition and heme utilization in A. paragallinarum from the perspective of transcriptomic profiles. The study will contribute to a better understanding of the transcriptomic response of A. paragallinarum to iron starvation and also provide novel insight into the development of new antigens for potential vaccines against infectious coryza by focusing on these iron-related genes.

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Transcriptional Response of Leptospira interrogans to Iron Limitation and Characterization of a PerR Homolog

Infection and Immunity ◽

10.1128/iai.00435-10 ◽

2010 ◽

Vol 78 (11) ◽

pp. 4850-4859 ◽

Cited By ~ 54

Author(s):

Miranda Lo ◽

Gerald L. Murray ◽

Chen Ai Khoo ◽

David A. Haake ◽

Richard L. Zuerner ◽

...

Keyword(s):

Oxidative Stress ◽

Stress Response ◽

Iron Homeostasis ◽

Storage Proteins ◽

Iron Acquisition ◽

Bacterial Species ◽

Transcriptional Response ◽

Oxidative Stress Response ◽

Wild Type ◽

In The Wild

ABSTRACT Leptospirosis is a globally significant zoonosis caused by Leptospira spp. Iron is essential for growth of most bacterial species. Since iron availability is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. In many bacteria, expression of iron uptake and storage proteins is regulated by Fur. L. interrogans encodes four predicted Fur homologs; we have constructed a mutation in one of these, la1857. We conducted microarray analysis to identify iron-responsive genes and to study the effects of la1857 mutation on gene expression. Under iron-limiting conditions, 43 genes were upregulated and 49 genes were downregulated in the wild type. Genes encoding proteins with predicted involvement in inorganic ion transport and metabolism (including TonB-dependent proteins and outer membrane transport proteins) were overrepresented in the upregulated list, while 54% of differentially expressed genes had no known function. There were 16 upregulated genes of unknown function which are absent from the saprophyte L. biflexa and which therefore may encode virulence-associated factors. Expression of iron-responsive genes was not significantly affected by mutagenesis of la1857, indicating that LA1857 is not a global regulator of iron homeostasis. Upregulation of heme biosynthetic genes and a putative catalase in the mutant suggested that LA1857 is more similar to PerR, a regulator of the oxidative stress response. Indeed, the la1857 mutant was more resistant to peroxide stress than the wild type. Our results provide insights into the role of iron in leptospiral metabolism and regulation of the oxidative stress response, including genes likely to be important for virulence.

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