Regulating iron storage and metabolism with RNA: an overview of posttranscriptional controls of intracellular iron homeostasis

2011 ◽  
Vol 3 (1) ◽  
pp. 26-36 ◽  
Author(s):  
Hubert Salvail ◽  
Eric Massé
Keyword(s):  
Iron Homeostasis ◽  
Intracellular Iron ◽  
Iron Storage

HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3915-3921 ◽  
Author(s):  
H.D. Riedel ◽  
M.U. Muckenthaler ◽  
S.G. Gehrke ◽  
I. Mohr ◽  
K. Brennan ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Regulatory Protein ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

scholarly journals Transcriptional profiling of Helicobacter pylori Fur- and iron-regulated gene expression

Microbiology ◽  
2005 ◽  
Vol 151 (2) ◽  
pp. 533-546 ◽  
Author(s):  
Florian D. Ernst ◽  
Stefan Bereswill ◽  
Barbara Waidner ◽  
Jeroen Stoof ◽  
Ulrike Mäder ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Iron Homeostasis ◽  
Transcriptional Profiling ◽  
Northern Hybridization ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Gastric Colonization ◽  
Genes Encoding ◽  
H Pylori ◽  
Regulated Gene Expression

Intracellular iron homeostasis is a necessity for almost all living organisms, since both iron restriction and iron overload can result in cell death. The ferric uptake regulator protein, Fur, controls iron homeostasis in most Gram-negative bacteria. In the human gastric pathogen Helicobacter pylori, Fur is thought to have acquired extra functions to compensate for the relative paucity of regulatory genes. To identify H. pylori genes regulated by iron and Fur, we used DNA array-based transcriptional profiling with RNA isolated from H. pylori 26695 wild-type and fur mutant cells grown in iron-restricted and iron-replete conditions. Sixteen genes encoding proteins involved in metal metabolism, nitrogen metabolism, motility, cell wall synthesis and cofactor synthesis displayed iron-dependent Fur-repressed expression. Conversely, 16 genes encoding proteins involved in iron storage, respiration, energy metabolism, chemotaxis, and oxygen scavenging displayed iron-induced Fur-dependent expression. Several Fur-regulated genes have been previously shown to be essential for acid resistance or gastric colonization in animal models, such as those encoding the hydrogenase and superoxide dismutase enzymes. Overall, there was a partial overlap between the sets of genes regulated by Fur and those previously identified as growth-phase, iron or acid regulated. Regulatory patterns were confirmed for five selected genes using Northern hybridization. In conclusion, H. pylori Fur is a versatile regulator involved in many pathways essential for gastric colonization. These findings further delineate the central role of Fur in regulating the unique capacity of H. pylori to colonize the human stomach.

In vivo tumor growth is inhibited by cytosolic iron deprivation caused by the expression of mitochondrial ferritin

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2428-2434 ◽  
Author(s):  
Guangjun Nie ◽  
Guohua Chen ◽  
Alex D. Sheftel ◽  
Kostas Pantopoulos ◽  
Prem Ponka
Keyword(s):  
Tumor Growth ◽  
Mammalian Cells ◽  
Iron Homeostasis ◽  
Rna Binding ◽  
Heme Oxygenase 1 ◽  
Iron Starvation ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Iron Regulatory Proteins ◽  
Mitochondrial Iron

Abstract Mitochondrial ferritin (MtFt) is a mitochondrial iron-storage protein whose function and regulation is largely unknown. Our previous results have shown that MtFt overexpression markedly affects intracellular iron homeostasis in mammalian cells. Using tumor xenografts, we examined the effects of MtFt overexpression on tumor iron metabolism and growth. The expression of MtFt dramatically reduced implanted tumor growth in nude mice. Mitochondrial iron deposition in MtFt-expressing tumors was directly observed by transmission electron microscopy. A cytosolic iron starvation phenotype in MtFt-expressing tumors was revealed by increased RNA-binding activity of iron regulatory proteins, and concomitantly both an increase in transferrin receptor levels and a decrease in cytosolic ferritin. MtFt overexpression also led to decreases in total cellular heme content and heme oxygenase-1 levels. In addition, elevated MtFt in tumors was also associated with a decrease in total aconitase activity and lower frataxin protein level. In conclusion, our study shows that high MtFt levels can significantly affect tumor iron homeostasis by shunting iron into mitochondria; iron scarcity resulted in partially deficient heme and iron-sulfur cluster synthesis. It is likely that deprivation of iron in the cytosol is the cause for the significant inhibition of xenograft tumor growth.

scholarly journals A Ferritin Mutant of Mycobacterium tuberculosis Is Highly Susceptible to Killing by Antibiotics and Is Unable To Establish a Chronic Infection in Mice

2012 ◽  
Vol 80 (10) ◽  
pp. 3650-3659 ◽  
Author(s):  
Ruchi Pandey ◽  
G. Marcela Rodriguez
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Iron Homeostasis ◽  
Storage Proteins ◽  
Iron Acquisition ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Content Type ◽  
Iron Storage Proteins

ABSTRACTIron is an essential, elusive, and potentially toxic nutrient for most pathogens, includingMycobacterium tuberculosis. Due to the poor solubility of ferric iron under aerobic conditions, free iron is not found in the host.M. tuberculosisrequires specialized iron acquisition systems to replicate and cause disease. It also depends on a strict control of iron metabolism and intracellular iron levels to prevent iron-mediated toxicity. Under conditions of iron sufficiency,M. tuberculosisrepresses iron acquisition and induces iron storage, suggesting an important role for iron storage proteins in iron homeostasis.M. tuberculosissynthesizes two iron storage proteins, a ferritin (BfrB) and a bacterioferritin (BfrA). The individual contributions of these proteins to the adaptive response ofM. tuberculosisto changes in iron availability are not clear. By generating individual knockout strains ofbfrAandbfrB, the contribution of each one of these proteins to the maintenance of iron homeostasis was determined. The effect of altered iron homeostasis, resulting from impaired iron storage, on the resistance ofM. tuberculosistoin vitroandin vivostresses was examined. The results show that ferritin is required to maintain iron homeostasis, whereas bacterioferritin seems to be dispensable for this function.M. tuberculosislacking ferritin suffers from iron-mediated toxicity, is unable to persist in mice, and, most importantly, is highly susceptible to killing by antibiotics, showing that endogenous oxidative stress can enhance the antibiotic killing of this important pathogen. These results are relevant for the design of new therapeutic strategies againstM. tuberculosis.

scholarly journals The Role of NCOA4-Mediated Ferritinophagy in Iron Homeostasis

2018 ◽  
Author(s):  
Naiara Santana-Codina ◽  
Joseph D. Mancias
Keyword(s):  
Iron Homeostasis ◽  
Iron Release ◽  
Intracellular Iron ◽  
Nuclear Receptor Coactivator ◽  
Iron Storage ◽  
Physiological Processes ◽  
Ferritin Iron ◽  
Autophagic Degradation ◽  
Dependent Cell

Nuclear receptor coactivator 4 (NCOA4) is a selective cargo receptor that mediates the autophagic degradation of ferritin (“ferritinophagy”), the cytosolic iron storage complex. NCOA4-mediated ferritinophagy maintains intracellular iron homeostasis by facilitating ferritin iron storage or release according to demand. Ferritinophagy is involved in iron-dependent physiological processes such as erythropoiesis, where NCOA4 mediates ferritin iron release for mitochondrial heme synthesis. Recently, ferritinophagy has been shown to regulate ferroptosis, a newly described form of iron-dependent cell death mediated by excess lipid peroxidation. Dysregulation of iron metabolism and ferroptosis have been described in neurodegeneration, cancer, and infection, but little is known about the role of ferritinophagy in the pathogenesis of these diseases. Here, we will review the biochemical regulation of NCOA4, its contribution to physiological processes and its role in disease. Finally, we will discuss the potential of activating or inhibiting ferritinophagy and ferroptosis for therapeutic purposes.

The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2564-2570 ◽  
Author(s):  
Hanqian Carlson ◽  
An-Sheng Zhang ◽  
William H. Fleming ◽  
Caroline A. Enns
Keyword(s):  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Cell Types ◽  
Single Amino Acid ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Transferrin Receptor 1 ◽  
A Cell

AbstractHereditary hemochromatosis (HH) is an autosomal recessive disease that leads to parenchymal iron accumulation. The most common form of HH is caused by a single amino acid substitution in the HH protein, HFE, but the mechanism by which HFE regulates iron homeostasis is not known. In the absence of transferrin (Tf), HFE interacts with transferrin receptor 1 (TfR1) and the 2 proteins co-internalize, and in vitro studies have shown that HFE and Tf compete for TfR1 binding. Using a cell line lacking endogenous transferrin receptors (TRVb cells) transfected with different forms of HFE and TfR1, we demonstrate that even at low concentrations Tf competes effectively with HFE for binding to TfR1 on living cells. Transfection of TRVb cells or the derivative line TRVb1 (which stably expresses human TfR1) with HFE resulted in lower ferritin levels and decreased Fe2+ uptake. These data indicate that HFE can regulate intracellular iron storage independently of its interaction with TfR1. Earlier studies found that in HeLa cells, HFE expression lowers Tf-mediated iron uptake; here we show that HFE lowers non–Tf-bound iron in TRVb cells and add to a growing body of evidence that HFE may play different roles in different cell types.

scholarly journals Mobilization of Iron Stored in Bacterioferritin Is Required for Metabolic Homeostasis in Pseudomonas aeruginosa

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 980
Author(s):  
Achala N. D. Punchi Hewage ◽  
Leo Fontenot ◽  
Jessie Guidry ◽  
Thomas Weldeghiorghis ◽  
Anil K. Mehta ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Culture Media ◽  
Acid Synthesis ◽  
Iron Limitation ◽  
Metabolic Homeostasis ◽  
Intracellular Iron ◽  
Amino Acid Synthesis ◽  
Iron Storage ◽  
Low Levels ◽  
Iron Storage Protein

Iron homeostasis offers a significant bacterial vulnerability because pathogens obtain essential iron from their mammalian hosts, but host-defenses maintain vanishingly low levels of free iron. Although pathogens have evolved mechanisms to procure host-iron, these depend on well-regulated iron homeostasis. To disrupt iron homeostasis, our work has targeted iron mobilization from the iron storage protein bacterioferritin (BfrB) by blocking a required interaction with its cognate ferredoxin partner (Bfd). The blockade of the BfrB–Bfd complex by deletion of the bfd gene (Δbfd) causes iron to irreversibly accumulate in BfrB. In this study we used mass spectrometry and NMR spectroscopy to compare the proteomic response and the levels of key intracellular metabolites between wild type (wt) and isogenic ΔbfdP. aeruginosa strains. We find that the irreversible accumulation of unusable iron in BfrB leads to acute intracellular iron limitation, even if the culture media is iron-sufficient. Importantly, the iron limitation and concomitant iron metabolism dysregulation trigger a cascade of events that lead to broader metabolic homeostasis disruption, which includes sulfur limitation, phenazine-mediated oxidative stress, suboptimal amino acid synthesis and altered carbon metabolism.

scholarly journals AmpI Functions as an Iron Exporter To Alleviate β-Lactam-Mediated Reactive Oxygen Species Stress in Stenotrophomonas maltophilia

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Yi-Wei Huang ◽  
Hsin-Hui Huang ◽  
Kai-Hung Huang ◽  
Wei-Chien Chen ◽  
Yi-Tsung Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stenotrophomonas Maltophilia ◽  
Iron Homeostasis ◽  
Reactive Oxygen ◽  
Iron Level ◽  
Oxygen Species ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Content Type ◽  
L1 And L2

ABSTRACT Stenotrophomonas maltophilia is an organism with a remarkable capacity for drug resistance with several antibiotic resistance determinants in its genome. S. maltophilia genome codes for L1 and L2, responsible for intrinsic β-lactam resistance. The Smlt3721 gene (denoted ampI), located downstream of the L2 gene, encodes an inner membrane protein. The existence of an L2 gene-ampI operon was verified by reverse transcription-PCR (RT-PCR). For aerobically grown S. maltophilia KJ, inactivation of ampI downregulated siderophore synthesis and iron acquisition systems and upregulated the iron storage system, as demonstrated by a transcriptome assay, suggesting that AmpI is involved in iron homeostasis. Compared with the wild-type KJ, an ampI mutant had an elevated intracellular iron level, as revealed by inductively coupled plasma mass spectrometry (ICP-MS) analysis, and increased sensitivity to H2O2, verifying the role of AmpI as an iron exporter. The β-lactam stress increased the intracellular reactive oxygen species (ROS) level and induced the expression of the L1 gene and L2 gene-ampI operon. Compared to its own parental strain, the ampI mutant had reduced growth in β-lactam-containing medium, and the ampI mutant viability was improved after complementation with plasmid pAmpI in either a β-lactamase-positive or β-lactamase-negative genetic background. Collectively, upon challenge with β-lactam, the inducibly expressed L1 and L2 β-lactamases contribute to β-lactam resistance by hydrolyzing β-lactam. AmpI functions as an iron exporter participating in rapidly weakening β-lactam-mediated ROS toxicity. The L1 gene and L2 gene-ampI operon enable S. maltophilia to effectively cope with β-lactam-induced stress.

scholarly journals Differential Role of Ferritins in Iron Metabolism and Virulence of the Plant-Pathogenic Bacterium Erwinia chrysanthemi 3937

2007 ◽  
Vol 190 (5) ◽  
pp. 1518-1530 ◽  
Author(s):  
Aïda Boughammoura ◽  
Berthold F. Matzanke ◽  
Lars Böttger ◽  
Sylvie Reverchon ◽  
Emmanuel Lesuisse ◽  
...  
Keyword(s):  
Gene Expression ◽  
Iron Homeostasis ◽  
Reverse Genetics ◽  
Bacterial Species ◽  
Erwinia Chrysanthemi ◽  
Intermediate Phenotype ◽  
Redox Stress ◽  
Intracellular Iron ◽  
Iron Storage

ABSTRACT During infection, the phytopathogenic enterobacterium Erwinia chrysanthemi has to cope with iron-limiting conditions and the production of reactive oxygen species by plant cells. Previous studies have shown that a tight control of the bacterial intracellular iron content is necessary for full virulence. The E. chrysanthemi genome possesses two loci that could be devoted to iron storage: the bfr gene, encoding a heme-containing bacterioferritin, and the ftnA gene, coding for a paradigmatic ferritin. To assess the role of these proteins in the physiology of this pathogen, we constructed ferritin-deficient mutants by reverse genetics. Unlike the bfr mutant, the ftnA mutant had increased sensitivity to iron deficiency and to redox stress conditions. Interestingly, the bfr ftnA mutant displayed an intermediate phenotype for sensitivity to these stresses. Whole-cell analysis by Mössbauer spectroscopy showed that the main iron storage protein is FtnA and that there is an increase in the ferrous iron/ferric iron ratio in the ftnA and bfr ftnA mutants. We found that ftnA gene expression is positively controlled by iron and the transcriptional repressor Fur via the small antisense RNA RyhB. bfr gene expression is induced at the stationary phase of growth. The σS transcriptional factor is necessary for this control. Pathogenicity tests showed that FtnA and the Bfr contribute differentially to the virulence of E. chrysanthemi depending on the host, indicating the importance of a perfect control of iron homeostasis in this bacterial species during infection.

scholarly journals Structure and function of a 9.6 megadalton bacterial iron storage compartment

2019 ◽  
Author(s):  
T. W. Giessen ◽  
B. J. Orlando ◽  
A. A. Verdegaal ◽  
M. G. Chambers ◽  
J. Gardener ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Storage Proteins ◽  
Essential Element ◽  
Redox Balance ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Storage Compartment ◽  
X Ray Crystallography ◽  
Iron Storage Proteins ◽  
Assembly Principles

AbstractIron storage proteins are essential for maintaining intracellular iron homeostasis and redox balance. Iron is generally stored in a soluble and bioavailable form inside ferritin protein compartments. However, some organisms do not encode ferritins and thus rely on alternative storage strategies. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment from Quasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo. We show that the cargo-loaded compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. These results form the basis for understanding alternate microbial strategies for dealing with the essential element iron.

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