scholarly journals The Regulator PerR Is Involved in Oxidative Stress Response and Iron Homeostasis and Is Necessary for Full Virulence of Streptococcus pyogenes

2002 ◽  
Vol 70 (9) ◽  
pp. 4968-4976 ◽  
Author(s):  
Susanna Ricci ◽  
Robert Janulczyk ◽  
Lars Björck
Keyword(s):  
Oxidative Stress ◽  
Streptococcus Pyogenes ◽  
Stress Responses ◽  
Metal Binding ◽  
Iron Homeostasis ◽  
Bacterial Species ◽  
Transcriptional Analysis ◽  
Wild Type ◽  
Allelic Replacement

ABSTRACT Ferric uptake regulator (Fur) and Fur-like proteins form an important family of transcriptional regulators in many bacterial species. In this work we have characterized a Fur-like protein, the peroxide regulator PerR, in an M1 serotype of Streptococcus pyogenes. To determine the role of PerR in S. pyogenes, we inactivated the gene by allelic replacement. PerR-deficient bacteria showed 48% reduction of 55Fe incorporation from the culture medium. Transcriptional analysis revealed that mtsA, encoding a metal-binding protein of an ABC transporter in S. pyogenes, was transcribed at lower levels than were wild-type cells. Although total iron accumulation was reduced, the growth of the mutant strain was not significantly hampered. The mutant showed hyperresistance to hydrogen peroxide, and this response was induced in wild-type cells by growth in aerobiosis, suggesting that PerR acts as an oxidative stress-responsive repressor. PerR may also participate in the response to superoxide stress, as the perR mutant was more sensitive to the superoxide anion and had a reduced transcription of sodA, which encodes the sole superoxide dismutase of S. pyogenes. Complementation of the mutation with a functional perR gene restored 55Fe incorporation, response to peroxide stress, and transcription of both mtsA and sodA to levels comparable to those of wild-type bacteria. Finally, the perR mutant was attenuated in virulence in a murine air sac model of infection (P < 0.05). These results demonstrate that PerR is involved in the regulation of iron homeostasis and oxidative stress responses and that it contributes to the virulence of S. pyogenes.

scholarly journals The Transcriptional Response to a Peroxisome Proliferator-activated Receptor α Agonist Includes Increased Expression of Proteome Maintenance Genes

2004 ◽  
Vol 279 (50) ◽  
pp. 52390-52398 ◽  
Author(s):  
Steven P. Anderson ◽  
Paul Howroyd ◽  
Jie Liu ◽  
Xun Qian ◽  
Rainer Bahnemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Proteasomal Genes ◽  
Oxidative Stress Responses

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARα in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARα-null mice. Primary hepatocytes from wild-type but not PPARα-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARα-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARα, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARα-null mice. Of the 815 genes regulated by WY in wild-type mice (p≤ 0.001; ≥1.5-fold or ≤-1.5-fold), only two genes were regulated similarly by WY in PPARα-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARα controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

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

2010 ◽  
Vol 78 (11) ◽  
pp. 4850-4859 ◽  
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.

scholarly journals Histone Deacetylase HDA-2 Regulates Trichoderma atroviride Growth, Conidiation, Blue Light Perception, and Oxidative Stress Responses

2016 ◽  
Vol 83 (3) ◽  
Author(s):  
Macario Osorio-Concepción ◽  
Gema Rosa Cristóbal-Mondragón ◽  
Braulio Gutiérrez-Medina ◽  
Sergio Casas-Flores
Keyword(s):  
Oxidative Stress ◽  
Histone Deacetylase ◽  
Blue Light ◽  
Stress Responses ◽  
Wild Type ◽  
Content Type ◽  
Encoding Gene ◽  
Oxidative Stress Responses ◽  
And Oxidative Stress

ABSTRACT Fungal blue-light photoreceptors have been proposed as integrators of light and oxidative stress. However, additional elements participating in the integrative pathway remain to be identified. In Trichoderma atroviride, the blue-light regulator (BLR) proteins BLR-1 and -2 are known to regulate gene transcription, mycelial growth, and asexual development upon illumination, and recent global transcriptional analysis revealed that the histone deacetylase-encoding gene hda-2 is induced by light. Here, by assessing responses to stimuli in wild-type and Δhda-2 backgrounds, we evaluate the role of HDA-2 in the regulation of genes responsive to light and oxidative stress. Δhda-2 strains present reduced growth, misregulation of the con-1 gene, and absence of conidia in response to light and mechanical injury. We found that the expression of hda-2 is BLR-1 dependent and HDA-2 in turn is essential for the transcription of early and late light-responsive genes that include blr-1, indicating a regulatory feedback loop. When subjected to reactive oxygen species (ROS), Δhda-2 mutants display high sensitivity whereas Δblr strains exhibit the opposite phenotype. Consistently, in the presence of ROS, ROS-related genes show high transcription levels in wild-type and Δblr strains but misregulation in Δhda-2 mutants. Finally, chromatin immunoprecipitations of histone H3 acetylated at Lys9/Lys14 on cat-3 and gst-1 promoters display low accumulation of H3K9K14ac in Δblr and Δhda-2 strains, suggesting indirect regulation of ROS-related genes by HDA-2. Our results point to a mutual dependence between HDA-2 and BLR proteins and reveal the role of these proteins in an intricate gene regulation landscape in response to blue light and ROS. IMPORTANCE Trichoderma atroviride is a free-living fungus commonly found in soil or colonizing plant roots and is widely used as an agent in biocontrol as it parasitizes other fungi, stimulates plant growth, and induces the plant defense system. To survive in various environments, fungi constantly sense and respond to potentially threatening external factors, such as light. In particular, UV light can damage biomolecules by producing free-radical reactions, in most cases involving reactive oxygen species (ROS). In T. atroviride, conidiation is essential for its survival, which is induced by light and mechanical injury. Notably, conidia are typically used as the inoculum in the field during biocontrol. Therefore, understanding the linkages between responses to light and exposure to ROS in T. atroviride is of major basic and practical relevance. Here, the histone deacetylase-encoding gene hda-2 is induced by light and ROS, and its product regulates growth, conidiation, blue light perception, and oxidative stress responses.

scholarly journals Syntaxin-17-Dependent Mitochondrial Dynamics is Essential for Protection Against Oxidative-Stress-Induced Apoptosis

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 522 ◽  
Author(s):  
Wang ◽  
Xiao ◽  
Huang ◽  
Liu
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Autophagic Flux ◽  
Wild Type ◽  
Dual Roles ◽  
Defective Mutant ◽  
U2os Cells ◽  
Induced Apoptosis

In this study, cell death induced by the oxidant tert-butylhydroperoxide (tBH) was observed in U2OS cells; this phenotype was rescued by Syntaxin 17 (STX17) knockout (KO) but the mechanism is unknown. STX17 plays dual roles in autophagosome–lysosome fusion and mitochondrial fission. However, the contribution of the two functions of STX17 to apoptosis has not been extensively studied. Here, we sought to dissect the dual roles of STX17 in oxidative-stress-induced apoptosis by taking advantage of STX17 knockout cells and an autophagosome–lysosome fusion defective mutant of STX17. We generated STX17 knockout U2OS cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and the STX17 knockout cells were reconstituted with wild-type STX17 and its autophagosome–lysosome fusion defective mutant. Autophagy was assessed by autophagic flux assay, Monomer red fluorescent protein (mRFP)–GFP–LC3 assay and protease protection assay. Golgi, endoplasmic reticulum (ER)/ER–Golgi intermediate compartment (ERGIC) and mitochondrial dynamics were examined by staining the different indicator proteins. Apoptosis was evaluated by caspase cleavage assay. The general reactive oxygen species (ROS) were detected by flow cytometry. In STX17 complete knockout cells, sealed autophagosomes were efficiently formed but their fusion with lysosomes was less defective. The fusion defect was rescued by wild-type STX17 but not the autophagosome–lysosome fusion defective mutant. No obvious defects in Golgi, ERGIC or ER dynamics were observed. Mitochondria were significantly elongated, supporting a role of STX17 in mitochondria fission and the elongation caused by STX17 KO was reversed by the autophagosome–lysosome fusion defective mutant. The clearance of protein aggregation was compromised, correlating with the autophagy defect but not with mitochondrial dynamics. This study revealed a mixed role of STX17 in autophagy, mitochondrial dynamics and oxidative stress response. STX17 knockout cells were highly resistant to oxidative stress, largely due to the function of STX17 in mitochondrial fission rather than autophagy.

scholarly journals Role of hepcidin in oxidative stress and cell death of cultured mouse renal collecting duct cells: protection against iron and sensitization to cadmium

2021 ◽  
Author(s):  
Stephanie Probst ◽  
Johannes Fels ◽  
Bettina Scharner ◽  
Natascha A. Wolff ◽  
Eleni Roussa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Fate ◽  
Catalase Activity ◽  
Metal Ion ◽  
Iron Homeostasis ◽  
Collecting Duct ◽  
Duct Cell ◽  
Plasmid Transfection

AbstractThe liver hormone hepcidin regulates systemic iron homeostasis. Hepcidin is also expressed by the kidney, but exclusively in distal nephron segments. Several studies suggest hepcidin protects against kidney damage involving Fe2+ overload. The nephrotoxic non-essential metal ion Cd2+ can displace Fe2+ from cellular biomolecules, causing oxidative stress and cell death. The role of hepcidin in Fe2+ and Cd2+ toxicity was assessed in mouse renal cortical [mCCD(cl.1)] and inner medullary [mIMCD3] collecting duct cell lines. Cells were exposed to equipotent Cd2+ (0.5–5 μmol/l) and/or Fe2+ (50–100 μmol/l) for 4–24 h. Hepcidin (Hamp1) was transiently silenced by RNAi or overexpressed by plasmid transfection. Hepcidin or catalase expression were evaluated by RT-PCR, qPCR, immunoblotting or immunofluorescence microscopy, and cell fate by MTT, apoptosis and necrosis assays. Reactive oxygen species (ROS) were detected using CellROX™ Green and catalase activity by fluorometry. Hepcidin upregulation protected against Fe2+-induced mIMCD3 cell death by increasing catalase activity and reducing ROS, but exacerbated Cd2+-induced catalase dysfunction, increasing ROS and cell death. Opposite effects were observed with Hamp1 siRNA. Similar to Hamp1 silencing, increased intracellular Fe2+ prevented Cd2+ damage, ROS formation and catalase disruption whereas chelation of intracellular Fe2+ with desferrioxamine augmented Cd2+ damage, corresponding to hepcidin upregulation. Comparable effects were observed in mCCD(cl.1) cells, indicating equivalent functions of renal hepcidin in different collecting duct segments. In conclusion, hepcidin likely binds Fe2+, but not Cd2+. Because Fe2+ and Cd2+ compete for functional binding sites in proteins, hepcidin affects their free metal ion pools and differentially impacts downstream processes and cell fate.

scholarly journals Critical Role of Zinc as Either an Antioxidant or a Prooxidant in Cellular Systems

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Sung Ryul Lee
Keyword(s):  
Oxidative Stress ◽  
Zinc Deficiency ◽  
Metal Binding ◽  
Inflammatory Responses ◽  
Binding Capacity ◽  
Critical Role ◽  
Cellular Systems ◽  
Oxidative Stresses ◽  
Dual Action

Zinc is recognized as an essential trace metal required for human health; its deficiency is strongly associated with neuronal and immune system defects. Although zinc is a redox-inert metal, it functions as an antioxidant through the catalytic action of copper/zinc-superoxide dismutase, stabilization of membrane structure, protection of the protein sulfhydryl groups, and upregulation of the expression of metallothionein, which possesses a metal-binding capacity and also exhibits antioxidant functions. In addition, zinc suppresses anti-inflammatory responses that would otherwise augment oxidative stress. The actions of zinc are not straightforward owing to its numerous roles in biological systems. It has been shown that zinc deficiency and zinc excess cause cellular oxidative stress. To gain insights into the dual action of zinc, as either an antioxidant or a prooxidant, and the conditions under which each role is performed, the oxidative stresses that occur in zinc deficiency and zinc overload in conjunction with the intracellular regulation of free zinc are summarized. Additionally, the regulatory role of zinc in mitochondrial homeostasis and its impact on oxidative stress are briefly addressed.

scholarly journals PmtA Regulates Pyocyanin Expression and Biofilm Formation in Pseudomonas aeruginosa

2021 ◽  
Vol 12 ◽  
Author(s):  
Amy V. Thees ◽  
Kathryn M. Pietrosimone ◽  
Clare K. Melchiorre ◽  
Jeremiah N. Marden ◽  
Joerg Graf ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pseudomonas Aeruginosa ◽  
Metal Binding ◽  
Biofilm Formation ◽  
Binding Capacity ◽  
Opportunistic Pathogen ◽  
Small Molecular Weight ◽  
Heavy Metal Binding ◽  
The Impact

The opportunistic pathogen Pseudomonas aeruginosa expresses a small molecular weight, cysteine-rich protein (PmtA), identified as a metallothionein (MT) protein family member. The MT family proteins have been well-characterized in eukaryotes as essential for zinc and copper homeostasis, protection against oxidative stress, and the ability to modify a variety of immune activities. Bacterial MTs share sequence homology, antioxidant chemistry, and heavy metal-binding capacity with eukaryotic MTs, however, the impact of bacterial MTs on virulence and infection have not been well-studied. In the present study, we investigated the role of PmtA in P. aeruginosa PAO1 using a PmtA-deficient strain (ΔpmtA). Here we demonstrated the virulence factor, pyocyanin, relies on the expression of PmtA. We showed that PmtA may be protective against oxidative stress, as an alternative antioxidant, glutathione, can rescue pyocyanin expression. Furthermore, the expression of phzM, which encodes a pyocyanin precursor enzyme, was decreased in the ΔpmtA mutant during early stationary phase. Upregulated pmtA expression was previously detected in confluent biofilms, which are essential for chronic infection, and we observed that the ΔpmtA mutant was disrupted for biofilm formation. As biofilms also modulate antibiotic susceptibility, we examined the ΔpmtA mutant susceptibility to antibiotics and found that the ΔpmtA mutant is more susceptible to cefepime and ciprofloxacin than the wild-type strain. Finally, we observed that the deletion of pmtA results in decreased virulence in a waxworm model. Taken together, our results support the conclusion that PmtA is necessary for the full virulence of P. aeruginosa and may represent a potential target for therapeutic intervention.

scholarly journals Roles of Autophagy in Oxidative Stress

2020 ◽  
Vol 21 (9) ◽  
pp. 3289 ◽  
Author(s):  
Hyeong Rok Yun ◽  
Yong Hwa Jo ◽  
Jieun Kim ◽  
Yoonhwa Shin ◽  
Sung Soo Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Stress Responses ◽  
Basic Mechanism ◽  
Redox Signalling ◽  
Mitochondrial Ros ◽  
Related Stress ◽  
And Function ◽  
Catabolic Process

Autophagy is a catabolic process for unnecessary or dysfunctional cytoplasmic contents by lysosomal degradation pathways. Autophagy is implicated in various biological processes such as programmed cell death, stress responses, elimination of damaged organelles and development. The role of autophagy as a crucial mediator has been clarified and expanded in the pathological response to redox signalling. Autophagy is a major sensor of the redox signalling. Reactive oxygen species (ROS) are highly reactive molecules that are generated as by-products of cellular metabolism, principally by mitochondria. Mitochondrial ROS (mROS) are beneficial or detrimental to cells depending on their concentration and location. mROS function as redox messengers in intracellular signalling at physiologically low level, whereas excessive production of mROS causes oxidative damage to cellular constituents and thus incurs cell death. Hence, the balance of autophagy-related stress adaptation and cell death is important to comprehend redox signalling-related pathogenesis. In this review, we attempt to provide an overview the basic mechanism and function of autophagy in the context of response to oxidative stress and redox signalling in pathology.

Role of lung iron in determining the bacterial and host struggle in cystic fibrosis

2009 ◽  
Vol 297 (5) ◽  
pp. L795-L802 ◽  
Author(s):  
D. W. Reid ◽  
G. J. Anderson ◽  
I. L. Lamont
Keyword(s):  
Cystic Fibrosis ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Genetic Disorder ◽  
Bacterial Species ◽  
System Disease ◽  
Liver And Pancreas ◽  
Pseudomonas Aeruginosa Infection ◽  
The Relationship

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.

scholarly journals Infused wild-type macrophages reside and self-renew in the liver to rescue the hemolysis and anemia of Hmox1-deficient mice

2018 ◽  
Vol 2 (20) ◽  
pp. 2732-2743 ◽  
Author(s):  
Ki Soon Kim ◽  
De-Liang Zhang ◽  
Gennadiy Kovtunovych ◽  
Manik C. Ghosh ◽  
Hayden Ollivierre ◽  
...  
Keyword(s):  
Stress Responses ◽  
Tissue Damage ◽  
Iron Homeostasis ◽  
Microcytic Anemia ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Intravascular Hemolysis ◽  
Hematopoietic Stem ◽  
Inflammatory Stress

AbstractHeme oxygenase 1 (HMOX1), the inducible enzyme that catabolizes the degradation of heme into biliverdin, iron, and carbon monoxide, plays an essential role in the clearance of senescent and damaged red blood cells, systemic iron homeostasis, erythropoiesis, vascular hemostasis, and oxidative and inflammatory stress responses. In humans, HMOX1 deficiency causes a rare and lethal disease, characterized by severe anemia, intravascular hemolysis, as well as vascular and tissue damage. Hmox1 knockout (KO) mice recapitulated the phenotypes of HMOX1-deficiency patients and could be rescued by bone marrow (BM) transplantation that engrafted donor’s hematopoietic stem cells into the recipient animals after myeloablation. To find better therapy and elucidate the contribution of macrophages to the pathogenesis of HMOX1-deficiency disease, we infused wild-type (WT) macrophages into Hmox1 KO mice. Results showed that WT macrophages engrafted and proliferated in the livers of Hmox1 KO mice, which corrected the microcytic anemia, rescued the intravascular hemolysis, restored iron homeostasis, eliminated kidney iron overload and tissue damage, and provided long-term protection. These results showed that a single macrophage infusion delivered a long-term curative effect in Hmox1 KO mice, obviating the need for BM transplantation, and suggested that the HMOX1 disease stems mainly from the loss of viable reticuloendothelial macrophages. Our work provides new insights into the etiology of HMOX1 deficiency and demonstrates the potential of infusion of WT macrophages to prevent disease in patients with HMOX1 deficiency and potentially other macrophage-related diseases.

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