Cadmium hijacks the high zinc response by binding and activating the HIZR-1 nuclear receptor

2021 ◽  
Vol 118 (42) ◽  
pp. e2022649118
Author(s):  
Brian J. Earley ◽  
Ciro Cubillas ◽  
Kurt Warnhoff ◽  
Raheel Ahmad ◽  
Alan Alcantar ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Health Hazard ◽  
Environmental Pollutant ◽  
Zinc Homeostasis ◽  
Nuclear Accumulation ◽  
Cadmium Resistance ◽  
High Zinc ◽  
Zinc Response ◽  
Zinc Resistance ◽  
Kinase Signaling Pathway

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In Caenorhabditis elegans, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1–mediated transcription via the high zinc activation (HZA) enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium, as well as a shared pathway.

scholarly journals Natural variation in the sequestosome-related gene, sqst-5, underlies zinc homeostasis in Caenorhabditis elegans

2020 ◽  
Author(s):  
Kathryn S. Evans ◽  
Stefan Zdraljevic ◽  
Lewis Stevens ◽  
Kimberly Collins ◽  
Robyn E. Tanny ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Caenorhabditis Elegans ◽  
Recombinant Inbred Lines ◽  
Zinc Homeostasis ◽  
Protein Domain ◽  
Zinc Binding ◽  
Related Gene ◽  
High Zinc ◽  
Zinc Response ◽  
Zinc Levels

AbstractZinc is an essential trace element that acts as a co-factor for many enzymes and transcription factors required for cellular growth and development. Altering intracellular zinc levels can produce dramatic effects ranging from cell proliferation to cell death. To avoid such fates, cells have evolved mechanisms to handle both an excess and a deficiency of zinc. Zinc homeostasis is largely maintained via zinc transporters, permeable channels, and other zinc-binding proteins. Variation in these proteins might affect their ability to interact with zinc, leading to either increased sensitivity or resistance to natural zinc fluctuations in the environment. We can leverage the power of the roundworm nematode Caenorhabditis elegans as a tractable metazoan model for quantitative genetics to identify genes that could underlie variation in responses to zinc. We found that the laboratory-adapted strain (N2) is resistant and a natural isolate from Hawaii (CB4856) is sensitive to micromolar amounts of exogenous zinc supplementation. Using a panel of recombinant inbred lines, we identified two large-effect quantitative trait loci (QTL) on the left arm of chromosome III and the center of chromosome V that are associated with zinc responses. We validated and refined both QTL using near-isogenic lines (NILs) and identified a naturally occurring deletion in sqst-5, a sequestosome-related gene, that is associated with resistance to high exogenous zinc. We found that this deletion is relatively common across strains within the species and that variation in sqst-5 is associated with zinc resistance. Our results offer a possible mechanism for how organisms can respond to naturally high levels of zinc in the environment and how zinc homeostasis varies among individuals.Author summaryZinc, although an essential metal, can be toxic if organisms are exposed to concentrations that are too high or too low. To prevent toxicity, organisms have evolved mechanisms to regulate zinc uptake from the environment. Here, we leveraged genetic variation between two strains of the roundworm Caenorhabditis elegans with different responses to high exogenous zinc to identify genes that might be involved in maintaining proper zinc levels. We identified four loci that contributed to differential zinc responses. One of these loci was the sequestosome-related gene sqst-5. We discovered that targeted deletions of sqst-5 caused an increase in resistance to zinc. Although SQST-5 contains a conserved zinc-binding protein domain, it has yet to be directly implicated in the C. elegans zinc response pathway. We identified two common forms of genetic variation in sqst-5 among 328 distinct strains, suggesting that variation in sqst-5 must have emerged multiple times, perhaps in response to an environment of high zinc. Overall, our study suggests a natural context for the evolution of zinc response mechanisms.

scholarly journals Cloning and Occurrence of czrC, a Gene Conferring Cadmium and Zinc Resistance in Methicillin-Resistant Staphylococcus aureus CC398 Isolates

2010 ◽  
Vol 54 (9) ◽  
pp. 3605-3608 ◽  
Author(s):  
L. M. Cavaco ◽  
H. Hasman ◽  
M. Stegger ◽  
P. S. Andersen ◽  
R. Skov ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Zinc Chloride ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Methicillin Resistance ◽  
Cadmium Acetate ◽  
Metal Resistance ◽  
Cadmium Resistance ◽  
Methicillin Resistant ◽  
Zinc Resistance ◽  
Animal Isolates

ABSTRACT We recently reported a phenotypic association between reduced susceptibility to zinc and methicillin resistance in Staphylococcus aureus CC398 isolates from Danish swine (F. M. Aarestrup, L. M. Cavaco, and H. Hasman, Vet. Microbiol. 142:455-457, 2009). The aim of this study was to identify the genetic determinant causing zinc resistance in CC398 and examine its prevalence in isolates of animal and human origin. Based on the sequence of the staphylococcal cassette chromosome mec (SCCmec) element from methicillin-resistant S. aureus (MRSA) CC398 strain SO385, a putative metal resistance gene was identified in strain 171 and cloned in S. aureus RN4220. Furthermore, 81 MRSA and 48 methicillin-susceptible S. aureus (MSSA) strains, isolated from pigs (31 and 28) and from humans (50 and 20) in Denmark, were tested for susceptibility to zinc chloride and for the presence of a putative resistance determinant, czrC, by PCR. The cloning of czrC confirmed that the zinc chloride and cadmium acetate MICs for isogenic constructs carrying this gene were increased compared to those for S. aureus RN4220. No difference in susceptibility to sodium arsenate, copper sulfate, or silver nitrate was observed. Seventy-four percent (n = 23) of the animal isolates and 48% (n = 24) of the human MRSA isolates of CC398 were resistant to zinc chloride and positive for czrC. All 48 MSSA strains from both human and pig origins were found to be susceptible to zinc chloride and negative for czrC. Our findings showed that czrC is encoding zinc and cadmium resistance in CC398 MRSA isolates, and that it is widespread both in humans and animals. Thus, resistance to heavy metals such as zinc and cadmium may play a role in the coselection of methicillin resistance in S. aureus.

scholarly journals Molecular Characterization of Cadmium Resistance in Streptococcus thermophilus Strain 4134: an Example of Lateral Gene Transfer

2002 ◽  
Vol 68 (11) ◽  
pp. 5508-5516 ◽  
Author(s):  
Jan Schirawski ◽  
Werner Hagens ◽  
Gerald F. Fitzgerald ◽  
Douwe van Sinderen
Keyword(s):  
Gene Transfer ◽  
Lateral Gene Transfer ◽  
Streptococcus Thermophilus ◽  
Dna Interaction ◽  
Negative Regulator ◽  
Cadmium Resistance ◽  
Mobility Shift ◽  
Transfer Event ◽  
Zinc Resistance

ABSTRACT Two genes (cadCSt and cadASt [subscript St represents Streptococcus thermophilus]), located on the chromosome of S. thermophilus 4134, were shown to constitute a cadmium/zinc resistance cassette. The genes seem to be organized in an operon, and their transcription is cadmium dependent in vivo. The proposed product of the cadA open reading frame (CadA St ) is highly similar to P-type cadmium efflux ATPases, whereas the predicted protein encoded by cadCSt (CadC St ) shows high similarity to ArsR-type regulatory proteins. The observed homologies and G+C content of this cassette and surrounding regions suggest that this DNA was derived from Lactococcus lactis and may have been introduced relatively recently into the S. thermophilus 4134 genome by a lateral gene transfer event. The complete cassette confers cadmium and zinc resistance to both S. thermophilus and L. lactis, but expression of cadASt alone is sufficient to give resistance. By using electrophoretic mobility shift assays it was shown that the CadC St protein is a DNA binding protein that binds specifically to its own promoter region, possibly to two copies of an inverted repeat, and that this CadC St -DNA interaction is lost in the presence of cadmium. Using lacZ fusion constructs it was shown that the cadmium-dependent expression of CadA St is mediated by the negative regulator CadC St . A model for the regulation of the expression of cadmium resistance in S. thermophilus is discussed.

Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid

2016 ◽  
Vol 91 (6) ◽  
pp. 2365-2374 ◽  
Author(s):  
Taiki Abe ◽  
Mirei Takahashi ◽  
Makoto Kano ◽  
Yuto Amaike ◽  
Chizuru Ishii ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
Perfluorooctanoic Acid ◽  
Environmental Pollutant

scholarly journals Ligand-Controlled Proteolysis of the Escherichia coli Transcriptional Regulator ZntR

2007 ◽  
Vol 189 (8) ◽  
pp. 3017-3025 ◽  
Author(s):  
Mihaela Pruteanu ◽  
Saskia B. Neher ◽  
Tania A. Baker
Keyword(s):  
Escherichia Coli ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Transcriptional Regulator ◽  
Zinc Homeostasis ◽  
Fine Tuning ◽  
Physical Analysis ◽  
Cellular Environment ◽  
High Zinc

ABSTRACT Proteases play a crucial role in remodeling the bacterial proteome in response to changes in cellular environment. Escherichia coli ZntR, a zinc-responsive transcriptional regulator, was identified by proteomic experiments as a likely ClpXP substrate, suggesting that protein turnover may play a role in regulation of zinc homeostasis. When intracellular zinc levels are high, ZntR activates expression of ZntA, an ATPase essential for zinc export. We find that ZntR is degraded in vivo in a manner dependent on both the ClpXP and Lon proteases. However, ZntR degradation decreases in the presence of high zinc concentrations, the level of ZntR rises, and transcription of the zntA exporter is increased. Mutagenesis experiments reveal that zinc binding does not appear to be solely responsible for the zinc-induced protection from proteolysis. Therefore, we tested whether DNA binding was important in the zinc-induced stabilization of ZntR by mutagenesis of the DNA binding helices. Replacement of a conserved arginine (R19A) in the DNA binding domain both enhances ZntR degradation and abolishes zinc-induced transcriptional activation of zntA. Biochemical and physical analysis of ZntRR19A demonstrates that it is structurally similar to, and binds zinc as well as does, the wild-type protein but is severely defective in binding DNA. Thus, we conclude that two different ligands—zinc and DNA—function together to increase ZntR stability and that ligand-controlled proteolysis of ZntR plays an important role in fine-tuning zinc homeostasis in bacteria.

scholarly journals The Nuclear Receptor HIZR-1 Uses Zinc as a Ligand to Mediate Homeostasis in Response to High Zinc

PLoS Biology ◽  
2017 ◽  
Vol 15 (1) ◽  
pp. e2000094 ◽  
Author(s):  
Kurt Warnhoff ◽  
Hyun C. Roh ◽  
Zuzana Kocsisova ◽  
Chieh-Hsiang Tan ◽  
Andrew Morrison ◽  
...  
Keyword(s):  
Nuclear Receptor ◽  
High Zinc

scholarly journals Investigating polystyrene nanoplastics-induced reproductive toxicity in vitro: Focus on Nrf2-PKM2-autophagy signaling pathway

2021 ◽  
Author(s):  
Siwen Li ◽  
Yu Ma ◽  
Shuzi Ye ◽  
Ying Su ◽  
Die Hu ◽  
...  
Keyword(s):  
Reproductive Toxicity ◽  
Environmental Pollutant ◽  
Nuclear Accumulation ◽  
Seminiferous Tubules ◽  
Related Factor ◽  
Mitochondrial Apoptosis ◽  
Inverted Microscope ◽  
Toxicity In Vitro ◽  
Nrf2 Protein

Abstract As an issue of widespread concern, microplastics pollution has emerged as a harmful environmental pollutant. Nanoplastics (NaPs) has reported to accumulate in the testes and cause degeneration in the seminiferous tubules. However, the current research involving NaPs-induced reproductive toxicity remains poorly understood. The current work aimed to investigate the mechanisms of NaPs-induced reproductive injury in vitro. At first, we found that 80 nm fluorescent NaPs could enter into GC-2spd(ts) cells by fluorescent inverted microscope. Our results also demonstrated that suppression of reactive oxygen species (ROS) inhibited NaPs-triggered mitochondrial apoptosis and autophagy in GC-2spd(ts) cells. We also found that NaPs treatment did not change the interaction between nuclear factor erythroid-derived 2-related factor (Nrf2) and Kelch-like ECH associated protein 1 (Keap1), while inhibiting nuclear accumulation of Nrf2 protein. Further in vitro experiments showed that NaPs-induced reproductive toxicity associated with reducing dimerize pyruvate kinase M2 (PKM2), which are ascribed to the loss of Nrf2. Meanwhile, improving nuclear accumulation of Nrf2 might interact with PKM2 to rescue mitochondrial apoptosis caused by NaPs. Together, this study highlight that disturbing Nrf2-PKM2 signaling is essential process of NaPs-induced reproductive toxicity and provide valuable insights into the mechanism of microplastics-induced reproductive toxicity.

scholarly journals A pathway for low zinc homeostasis that is conserved in animals and acts in parallel to the pathway for high zinc homeostasis

2017 ◽  
Vol 45 (20) ◽  
pp. 11658-11672 ◽  
Author(s):  
Nicholas Dietrich ◽  
Daniel L. Schneider ◽  
Kerry Kornfeld
Keyword(s):  
Zinc Homeostasis ◽  
High Zinc

The influence of the trace element zinc on the immune system

2015 ◽  
Vol 39 (3) ◽  
Author(s):  
Claudia Schubert ◽  
Karina Guttek ◽  
Annegret Reinhold ◽  
Kurt Grüngreiff ◽  
Dirk Reinhold
Keyword(s):  
Immune System ◽  
Autoimmune Diseases ◽  
Trace Element ◽  
Adaptive Immune System ◽  
Zinc Homeostasis ◽  
Immune Functions ◽  
Immunological Parameters ◽  
High Zinc ◽  
Zinc Concentrations

AbstractClinical and experimental examinations showed a close relationship between zinc as an essential trace element and the immune system. Thus, cellular and humoral components from both the innate and the adaptive immune system are affected by zinc. Human zinc deficiencies are frequently connected with disturbed immune functions. Controlled zinc substitution results in a normalization of zinc serum levels, zinc homeostasis, and the immunological parameters. As shown in in vitro experiments, low zinc concentrations stimulate functional parameters of immune cells, but high zinc concentrations are suppressive or cytotoxic for these cells. Recently, the immunosuppressive effect of zinc was demonstrated in animal models of T-cell-dependent autoimmune diseases, like experimental autoimmune encephalomyelitis. Moreover, decreased serum/plasma zinc concentrations have been detected in patients with different autoimmune diseases. Prospective studies should verify the possibility of controlled immunosuppressive zinc therapies for these diseases.

scholarly journals Interplay of the Czc System and Two P-Type ATPases in Conferring Metal Resistance to Ralstonia metallidurans

2003 ◽  
Vol 185 (15) ◽  
pp. 4354-4361 ◽  
Author(s):  
Antje Legatzki ◽  
Gregor Grass ◽  
Andreas Anton ◽  
Christopher Rensing ◽  
Dietrich H. Nies
Keyword(s):  
Efflux Pump ◽  
Single Gene ◽  
Metal Resistance ◽  
Cadmium Resistance ◽  
Gene Deletions ◽  
Double Deletion ◽  
Induction Pattern ◽  
Ralstonia Metallidurans ◽  
P Type ◽  
Zinc Resistance

ABSTRACT Cadmium and zinc are removed from cells of Ralstonia metallidurans by the CzcCBA efflux pump and by two soft-metal-transporting P-type ATPases, CadA and ZntA. The czcCBA genes are located on plasmid pMOL30, and the cadA and zntA genes are on the bacterial chromosome. Expression of zntA from R. metallidurans in Escherichia coli predominantly mediated resistance to zinc, and expression of cadA predominantly mediated resistance to cadmium. Both transporters decreased the cellular content of zinc or cadmium in this host. In the plasmid-free R. metallidurans strain AE104, single gene deletions of cadA or zntA had only a moderate effect on cadmium and zinc resistance, but zinc resistance decreased 6-fold and cadmium resistance decreased 350-fold in double deletion strains. Neither single nor double gene deletions affected zinc resistance in the presence of czcCBA. In contrast, cadmium resistance of the cadA zntA double mutant could be elevated only partially by the presence of CzcCBA. lacZ reporter gene fusions indicated that expression of cadA was induced by cadmium but not by zinc in R. metallidurans strain AE104. In the absence of the zntA gene, expression of cadA occurred at lower cadmium concentrations and zinc now served as an inducer. In contrast, expression of zntA was induced by both zinc and cadmium, and the induction pattern did not change in the presence or absence of CadA. However, expression of both genes, zntA and cadA, was diminished in the presence of CzcCBA. This indicated that CzcCBA efficiently decreased cytoplasmic cadmium and zinc concentrations. It is discussed whether these data favor a model in which the cations are removed either from the cytoplasm or the periplasm by CzcCBA.

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