scholarly journals Bacterioferritin: a key iron storage modulator that affects strain growth and butenyl-spinosyn biosynthesis in Saccharopolyspora pogona

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Jianli Tang ◽  
Zirong Zhu ◽  
Haocheng He ◽  
Zhudong Liu ◽  
Ziyuan Xia ◽  
...  
Keyword(s):  
Stress Resistance ◽  
Quantitative Proteomics ◽  
Polyketide Synthase ◽  
Storage Capacity ◽  
Oxidative Stress Response ◽  
Iron Toxicity ◽  
Intracellular Iron ◽  
Proteomics Analysis ◽  
Iron Storage

Abstract Background Butenyl-spinosyn, produced by Saccharopolyspora pogona, is a promising biopesticide due to excellent insecticidal activity and broad pesticidal spectrum. Bacterioferritin (Bfr, encoded by bfr) regulates the storage and utilization of iron, which is essential for the growth and metabolism of microorganisms. However, the effect of Bfr on the growth and butenyl-spinosyn biosynthesis in S. pogona has not been explored. Results Here, we found that the storage of intracellular iron influenced butenyl-spinosyn biosynthesis and the stress resistance of S. pogona, which was regulated by Bfr. The overexpression of bfr increased the production of butenyl-spinosyn by 3.14-fold and enhanced the tolerance of S. pogona to iron toxicity and oxidative damage, while the knockout of bfr had the opposite effects. Based on the quantitative proteomics analysis and experimental verification, the inner mechanism of these phenomena was explored. Overexpression of bfr enhanced the iron storage capacity of the strain, which activated polyketide synthase genes and enhanced the supply of acyl-CoA precursors to improve butenyl-spinosyn biosynthesis. In addition, it induced the oxidative stress response to improve the stress resistance of S. pogona. Conclusion Our work reveals the role of Bfr in increasing the yield of butenyl-spinosyn and enhancing the stress resistance of S. pogona, and provides insights into its enhancement on secondary metabolism, which provides a reference for optimizing the production of secondary metabolites in actinomycetes.

scholarly journals Comparative Proteomics Analysis of Mouse Habu Nephritis Models with and without Unilateral Nephrectomy

2016 ◽  
Vol 39 (5) ◽  
pp. 1761-1776 ◽  
Author(s):  
Lei Chen ◽  
Yang Lu ◽  
Jun Wen ◽  
Xu Wang ◽  
Lingling Wu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Quantitative Proteomics ◽  
Mesangial Cells ◽  
Unilateral Nephrectomy ◽  
Label Free ◽  
Proteomics Analysis ◽  
Single Kidney ◽  
Regulation Of Actin Cytoskeleton ◽  
Insight Into

Background/Aims: Individuals possessing a single kidney are at greater risk of renal injury upon exposure to harmful stimuli. This study aimed to explore the pathogenesis of renal injury in glomerulonephritis with versus without unilateral nephrectomy (UNX). Methods: Histological analysis and label-free quantitative proteomics were performed on two models—the Habu snake venom-induced glomerulonephritis model with versus without UNX (HabuU and Habu models, respectively). The role of villin 1, a differentially expressed protein (DEP) in mouse mesangial cells, was investigated. Results: Persistent mesangiolysis and focal hypercellularity together with reduced activation of cell proliferation in the HabuU model induced more serious renal injury compared with that in the Habu model. The DEPs between the two models were identified by label-free liquid chromatography-mass spectrometry. The KEGG pathway results indicated that regulation of actin cytoskeleton and focal adhesion were specifically enriched in the HabuU model. The cytoskeleton regulation protein villin 1 was downregulated in the HabuU model, but unchanged in the Habu model. Knockdown of villin 1 promoted apoptosis and inhibited the proliferation of mouse mesangial cells, suggesting villin 1 to be involved in qlomerular lesion self-repair insufficiency. Conclusion: By assessing the proteomic profiles of the two models, this study identified several important differences, particularly villin 1 expression, in regulatory mechanisms between the two models. Our findings provide novel insight into the mechanism of serious renal injury in glomerulonephritis with UNX.

Tumor Cell Cytotoxicity of a Novel Metal Chelator

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1384-1389 ◽  
Author(s):  
S.V. Torti ◽  
F.M. Torti ◽  
S.P. Whitman ◽  
M.W. Brechbiel ◽  
G. Park ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Metal Chelator ◽  
Pendant Arm ◽  
Ferritin Synthesis ◽  
Bladder Cancer Cells ◽  
Sterically Hindered ◽  
American Society

Abstract We have synthesized a novel six-coordinate metal chelator from the triamine cis-1,3,5-triaminocyclohexane by the addition of a 2-pyridylmethyl pendant arm on each nitrogen, which we term tachpyr. The experiments described here were designed to explore whether this compound exhibits potential antitumor activity. When added to MBT2 or T24 cultured bladder cancer cells, tachpyr was profoundly cytotoxic, with an IC50 of approximately 4.6 μmol/L compared with 70 μmol/L for desferioxamine. To explore the mode of action of tachpyr, several metal complexes were prepared, including Fe(II), Ca(II), Mn(II), Mg(II), Cu(II), and Zn(II) tachpyr complexes. Of these, the Zn(II), Cu(II), and Fe(II) complexes were without toxic effect, whereas the Ca(II), Mn(II), and Mg(II) complexes remained cytotoxic. To further probe the role of Zn(II) and Cu(II) chelation in the cytotoxicity of tachpyr, sterically hindered tachpyr derivatives were prepared through N-alkylation of tachpyr. These derivatives were unable to strongly bind Fe(III) or Fe(II) but were able to bind Zn(II) and Cu(II). When added to cells, these sterically hindered tachpyr derivatives were nontoxic, consistent with a role of iron depletion in the cytotoxic mechanism of tachpyr. Further, the addition of tachpyr to proliferating cultures resulted in an early and selective inhibition of ferritin synthesis, an iron storage protein whose translation is critically dependent on intracellular iron pools. Taken together, these experiments suggest that tachpyr is a cytotoxic metal chelator that targets intracellular iron, and that the use of tachpyr in cancer therapy deserves further exploration. © 1998 by The American Society of Hematology.

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 Synchrotron-Based Nano-XANES Reveals Intracellular Heterogeneity of Iron Species in Magnetotactic Bacteria

2021 ◽  
Author(s):  
Daniel Chevrier ◽  
Elisa Cerdá-Doñate ◽  
Yeseul Park ◽  
Fernando Cacho-Nerin ◽  
Miguel Gomez-Gonzalez ◽  
...  
Keyword(s):  
Cell Level ◽  
Iron Species ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Edge Structure ◽  
X Ray ◽  
Magnetite Biomineralization ◽  
Iron Material ◽  
X Ray Absorption

<p>This report demonstrates how scanning X-ray fluorescence microscopy (SXFM) and nanoscale X-ray absorption near-edge structure (nano-XANES) can spatially and chemically identify intracellular iron species at the single-cell level, creating an opportunity to examine the role of iron storage in magnetite biomineralization. Fe K-edge nano-XANES measurements of <i>Magnetospirillum gryphiswaldense</i> in varied iron media conditions and iron storage capacity revealed intracellular iron heterogeneities through a distinction between formed magnetosomes and intracellular iron material. This work highlights the potential of nano-XANES in providing an experimental advantage in the multidisciplinary field of biomineralization.</p>

The OxrA protein of Aspergillus fumigatus is required for the oxidative stress response and fungal pathogenesis

2021 ◽  
Author(s):  
Pengfei Zhai ◽  
Landan Shi ◽  
Guowei Zhong ◽  
Jihong Jiang ◽  
Jingwen Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Immune Response ◽  
Stress Resistance ◽  
Pathogenic Fungi ◽  
Oxidative Stress Response ◽  
Fungal Pathogenesis ◽  
Oxygen Species ◽  
Oxidative Stress Resistance

An efficient reactive oxygen species (ROS) detoxification system is vital for the survival of the pathogenic fungus Aspergillus fumigatus within the host high ROS environment of the host. Therefore, identifying and targeting factors essential for oxidative stress response is one approach to develop novel treatments for fungal infections. Oxidation resistance 1 (Oxr1) protein is essential for protection against oxidative stress in mammals, but its functions in pathogenic fungi remain unknown. The present study aimed to characterize the role of an Oxr1 homolog in A. fumigatus . The results indicated that the OxrA protein plays an important role in oxidative stress resistance by regulating the catalase function in A. fumigatus , and overexpression of catalase can rescue the phenotype associated with OxrA deficiency. Importantly, the deficiency of oxrA decreased the virulence of A. fumigatus and altered the host immune response. Using the Aspergillus -induced lung infection model, we demonstrated that the ΔoxrA mutant strain induced less tissue damage along with decreased levels of LDH and albumin release. Additionally, the ΔoxrA mutant caused inflammation at a lower degree, along with a markedly reduced influx of neutrophils to the lungs and a decreased secretion of cytokine usually associated with recruitment of neutrophils in mice. These results characterize for the role of OxrA in A. fumigatus , as a core regulator of oxidative stress resistance and fungal pathogenesis. Importance Knowledge of reactive oxygen species (ROS) detoxification in fungal pathogens is useful in the design of new antifungal drugs and could aid in the study of oxidative stress resistance mechanisms. In this study, we demonstrate that OxrA protein localize to the mitochondria and function to protect against oxidative damage. We demonstrate that OxrA contributes to oxidative stress resistance by regulating catalase function, and overexpression of catalase (CatA or CatB) can rescue the phenotype that is associated with OxrA deficiency. Remarkably, a loss of OxrA attenuated the fungal virulence in a mouse model of invasive pulmonary aspergillosis and altered the host immune response. Therefore, our finding indicates that inhibition of OxrA might be an effective approach for alleviating A. fumigatus infection. The present study is, to the best of our knowledge, a pioneer in reporting the vital role of Oxr1 protein in pathogenic fungi.

scholarly journals IdeR, a DtxR Family Iron Response Regulator, Controls Iron Homeostasis, Morphological Differentiation, Secondary Metabolism, and the Oxidative Stress Response inStreptomyces avermitilis

2018 ◽  
Vol 84 (22) ◽  
Author(s):  
Yaqing Cheng ◽  
Renjun Yang ◽  
Mengya Lyu ◽  
Shiwei Wang ◽  
Xingchao Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Secondary Metabolism ◽  
Iron Homeostasis ◽  
Morphological Differentiation ◽  
Oxidative Stress Response ◽  
Regulatory Role ◽  
Intracellular Iron ◽  
Content Type

ABSTRACTIron, an essential element for microorganisms, functions as a vital cofactor in a wide variety of key metabolic processes. On the other hand, excess iron may have toxic effects on bacteria by catalyzing the formation of reactive oxygen species through the Fenton reaction. The prevention of iron toxicity requires the precise control of intracellular iron levels in bacteria. Mechanisms of iron homeostasis in the genusStreptomyces(the producers of various antibiotics) are poorly understood.Streptomyces avermitilisis the industrial producer of avermectins, which are potent anthelmintic agents widely used in medicine, agriculture, and animal husbandry. We investigated the regulatory role of IdeR, a DtxR family regulator, inS. avermitilis. In the presence of iron, IdeR binds to a specific palindromic consensus sequence in promoters and regulates 14 targets involved in iron metabolism (e.g., iron acquisition, iron storage, heme metabolism, and Fe-S assembly). IdeR also directly regulates 12 targets involved in other biological processes, including morphological differentiation, secondary metabolism, carbohydrate metabolism, and the tricarboxylic acid (TCA) cycle.ideRtranscription is positively regulated by the peroxide-sensing transcriptional regulator OxyR. A newly constructedideRdeletion mutant (DideR) was found to be less responsive to iron levels and more sensitive to H2O2treatment than the wild-type strain, indicating thatideRis essential for oxidative stress responses. Our findings, taken together, demonstrate that IdeR plays a pleiotropic role in the overall coordination of metabolism inStreptomycesspp. in response to iron levels.IMPORTANCEIron is essential to almost all organisms, but in the presence of oxygen, iron is both poorly available and potentially toxic.Streptomycesspecies are predominantly present in soil where the environment is complex and fluctuating. So far, the mechanism of iron homeostasis inStreptomycesspp. remains to be elucidated. Here, we characterized the regulatory role of IdeR in the avermectin-producing organismS. avermitilis. IdeR maintains intracellular iron levels by regulating genes involved in iron absorption and storage. IdeR also directly regulates morphological differentiation, secondary metabolism, and central metabolism.ideRis under the positive control of OxyR and is indispensable for an efficient response to oxidative stress. This investigation uncovered that IdeR acts as a global regulator coordinating iron homeostasis, morphological differentiation, secondary metabolism, and oxidative stress response inStreptomycesspecies. Elucidation of the pleiotropic regulation function of IdeR provides new insights into the mechanisms of howStreptomycesspp. adapt to the complex environment.

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 The Role of Iron in the Pathogenesis of Atherosclerosis

2017 ◽  
pp. S55-S67 ◽  
Author(s):  
P. KRAML
Keyword(s):  
Cardiovascular Risk ◽  
Free Oxygen Radicals ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Oxidation Stress ◽  
Iron Stores ◽  
Labile Iron Pool ◽  
Labile Iron ◽  
Iron Pool

Ferritin and increased iron stores first appeared on the list of cardiovascular risk factors more than 30 years ago and their causal role in the pathogenesis of atherosclerosis has been heavily discussed since the early 1990s. It seems that besides traditional factors such as hyperlipoproteinemia, hypertension, diabetes mellitus, obesity, physical inactivity, smoking and family history, high iron stores represent an additional parameter that could modify individual cardiovascular risk. The role of iron in the pathogenesis of atherosclerosis was originally primarily associated with its ability to catalyze the formation of highly reactive free oxygen radicals and the oxidation of atherogenic lipoproteins. Later, it became clear that the mechanism is more complex. Atherosclerosis is a chronic fibroproliferative inflammatory process and iron, through increased oxidation stress as well as directly, can control both native and adaptive immune responses. Within the arterial wall, iron affects all of the cell types that participate in the atherosclerotic process (monocytes/macrophages, endothelial cells, vascular smooth muscle cells and platelets). Most intracellular iron is bound in ferritin, whereas redox-active iron forms labile iron pool. Pro-inflammatory and anti-inflammatory macrophages within arterial plaque differ with regard to the amount of intracellular iron and most probably with regard to their labile iron pool. Yet, the relation between plasma ferritin and intracellular labile iron pool has not been fully clarified. Data from population studies document that the consumption of meat and lack of physical activity contribute to increased iron stores. Patients with hereditary hemochromatosis, despite extreme iron storage, do not show increased manifestation of atherosclerosis probably due to the low expression of hepcidin in macrophages.

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 (&ldquo;ferritinophagy&rdquo;), 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.

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