Global analysis of the zinc homeostasis network in Pseudomonas aeruginosa (DOI: 10.3389/fmicb.2021.739988)
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PROVIDER: PRJNA758984 | ENA |
REPOSITORIES: ENA
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Project description:In this study we followed up the dynamics of all genes involved in zinc homeostasis in Pseudomonas aeruginosa from starvation to excess, as it happens during infection. The results showed a hierarchical induction of the export systems and a global repression of import mechanisms
2021-10-27 | GSE183060 | GEO
Project description:This study addresses the impact of zinc limitation on the opportunistic human pathogen, Pseudomonas aeruginosa. Zinc limitation was assessed in the P. aeruginosa PAO1 strain using an isogenic deletion mutant lacking the periplasmic, zinc solute-binding protein, znuA (PA5498). ZnuA delivers bound zinc to its cognate ABC transporter, ZnuBC, for import into the cytoplasm. Our transcriptional analyses revealed P. aeruginosa to possess a multitude of zinc acquisition mechanisms, each of which were highly up-regulated in the zinc-deficient znuA mutant strain. P. aeruginosa also utilized zinc-independent paralogues of zinc-dependent genes to maintain cellular function under zinc limitation. Together, these data reveal the complex transcriptional response and versatility of P. aeruginosa to zinc depletion.
2017-01-01 | GSE60177 | GEO
Project description:Zinc is an essential element for animals and stored in de novo synthesized lysosome related organelles called bilobed granules in Caenorhabditis elegans. Defining how zinc regulated transcription drives the observed lysosome remodeling is key to understand zinc homeostasis processes. Here we describe a positively regulated zinc network controlled by HIZR-1 and HLH-30, the zinc sensor and the master regulator of the autophagy-lysosomal pathway in Caenorhabditis elegans, respectively; essential for connecting zinc homeostasis to lysosome biogenesis. Our studies indicate that either hizr-1 and hlh-30 are necessary and sufficient to activate transcription of lysosome-genes under high dietary zinc conditions. Consistent with the hizr-1 and hlh-30 dependency for high zinc response, we found DNA enhancer elements corresponding to the high zinc activation element consistently adjacent to E-boxes in the promoter regions of lysosome-genes. We defined a regulatory network based on the contribution of each transcription factor. Since zinc cannot be degraded, the autophagy-lysosomal pathway could play a key role in removing zinc excess
2021-05-15 | GSE172079 | GEO
Project description:<p><em>Streptococcus pneumoniae</em> is the primary cause of community-acquired bacterial pneumonia with rates of penicillin and multi-drug resistance exceeding 80% and 40%, respectively. The innate immune response generates a variety of antimicrobial agents to control infection including zinc stress. Here, we characterized the impact of zinc intoxication on <em>S. pneumoniae</em>, revealing disruptions in central carbon metabolism, lipid biogenesis and peptidoglycan biosynthesis. Characterization of the pivotal peptidoglycan biosynthetic enzyme GlmU revealed an exquisite sensitivity to zinc inhibition. Disruption of the sole zinc efflux pathway, czcD, rendered <em>S. pneumonia</em>e highly susceptible to β-lactam antibiotics. To dysregulate zinc homeostasis in the wild-type strain, we investigated the safe-for-human use ionophore PBT2. PBT2 rendered wild-type <em>S. pneumoniae</em> strains sensitive to a range of antibiotics. Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2+ampicillin treatment. These findings present a therapeutic modality to break resistance of drug-resistant <em>S. pneumoniae</em>.</p>
2022-02-23 | MTBLS318 | MetaboLights
Project description:We previously identified the ZTRE in genes involved in zinc homeostasis and showed that it mediates transcriptional repression in response to zinc. We now report that ZNF658 acts at the ZTRE. ZNF658 was identified by MALDI-TOF mass spectrometry of a band excised after EMSA using a ZTRE probe. The protein contains a KRAB domain and 21 zinc fingers. It has similarity with ZAP1 from Saccharomyces cerevisiae, which regulates the response to zinc restriction, including a conserved DNA binding region we show to be functional also in ZNF658. siRNA targeted to ZNF658 abrogated the zinc-induced, ZTRE-dependent reduction in SLC30A5 (ZnT5), SLC30A10 (ZnT10) and CBWD transcripts in human Caco-2 cells and the ability of zinc to repress reporter gene expression from corresponding promoter-reporter constructs. Microarray analysis of the effect of reducing ZNF658 expression by siRNA uncovered large changes in rRNA. We find that ZTREs are clustered within the 45S rRNA precursor. We also saw effects on expression of multiple ribosomal proteins. ZNF658 thus links zinc homeostasis with ribosome biogenesis, the most active transcriptional, and hence zinc-demanding, process in the cell. ZNF658 is thus a novel transcriptional regulator that plays a fundamental role in the orchestrated cellular response to zinc availability.
2014-12-31 | GSE59385 | GEO
Project description:The zinc-responsive repressor Loz1 is the master regulator of zinc homeostasis in Schizosaccharomyces pombe
| PRJNA541560 | ENA
Project description:EOS1 is required for tolerance to oxidative stress in Saccharomyces cerevisiae; mutants are defective in the gene sensitive to hydrogen peroxide and tolerant to tunicamycin. To clarify the function of Eos1, we screened yeast genomic DNA libraries for heterologous genes that, when overexpressed from a plasmid, can suppress the hydrogen peroxide-sensitive eos1 mutation. We identified such a gene as IZH2, which has previously been reported to be a Zap1-regulated gene. However, the EOS1 and IZH2 genes do not themselves appear to be functionally interchangeable. Double disruption of the EOS1 and IZH2 genes yielded a slow-growth phenotype, suggesting that the two proteins are involved in related cellular processes. DNA microarray analysis revealed decreased expression of Zap1-regulated genes in the eos1-deletion mutant (delta eos1). Thus, it is likely that Eos1 is involved in zinc homeostasis. Yeast cells were cultivated in YPD at 30 oC with shaking at 150 rpm, and then the cells were harvested at the log phase (OD600=1.0). Affymetrix Yeast Genome 2.0 arrays (Affymetrix, Santa Clara, CA, USA) were used as the DNA microarrays. Statistical analysis of the expression data were performed using GeneSpring ver. 7.3.1 (Agilent Technologies, Palo Alto, CA, USA) based on the gene expression data from two independent experiments.
2010-04-12 | E-GEOD-18310 | biostudies-arrayexpress
Project description:BACKGROUND: The zinc homeostasis system in Escherichia coli is one of the most intensively studied prokaryotic zinc homeostasis systems. Its underlying regulatory machine consists of repression on zinc influx through ZnuABC by Zur (Zn2+ uptake regulator) and activation on zinc efflux via ZntA by ZntR (a zinc-responsive regulator). Although these transcriptional regulations seem to be well characterized, and there is an abundance of detailed in vitro experimental data available, as yet there is no mathematical model to help interpret these data. To our knowledge, the work described here is the first attempt to use a mathematical model to simulate these regulatory relations and to help explain the in vitro experimental data. RESULTS: We develop a unified mathematical model consisting of 14 reactions to simulate the in vitro transcriptional response of the zinc homeostasis system in E. coli. Firstly, we simulate the in vitro Zur-DNA interaction by using two of these reactions, which are expressed as 4 ordinary differential equations (ODEs). By imposing the conservation restraints and solving the relevant steady state equations, we find that the simulated sigmoidal curve matches the corresponding experimental data. Secondly, by numerically solving the ODEs for simulating the Zur and ZntR run-off transcription experiments, and depicting the simulated concentrations of zntA and znuC transcripts as a function of free zinc concentration, we find that the simulated curves fit the corresponding in vitro experimental data. Moreover, we also perform simulations, after taking into consideration the competitive effects of ZntR with the zinc buffer, and depict the simulated concentration of zntA transcripts as a function of the total ZntR concentration, both in the presence and absence of Zn(II). The obtained simulation results are in general agreement with the corresponding experimental data. CONCLUSION: Simulation results show that our model can quantitatively reproduce the results of several of the in vitro experiments conducted by Outten CE and her colleagues. Our model provides a detailed insight into the dynamics of the regulatory system and also provides a general framework for simulating in vitro metal-binding and transcription experiments and interpreting the relevant experimental data.
2024-09-02 | BIOMD0000000966 | BioModels
Project description:Hypomorphic ASGR1 Modulates Lipid Homeostasis via SREBPs Network
| PRJNA738702 | ENA
Project description:Invasive fungal infections (IFIs) are difficult to treat. Few effective antifungal drugs are available and many have problems with toxicity, efficacy and drug-resistance. To overcome these challenges, existing therapies may be enhanced using more than one agent acting in synergy. Previously, we have found amphotericin B (AMB) and the iron chelator, lactoferrin (LF), were synergistic against Cryptococcus neoformans and Saccharomyces cerevisiae. This study investigates the mechanism of AMB+LF synergy, using RNA-seq and network analyses. Genes involved in iron homeostasis showed increased expression upon treatment with AMB alone. Unexpectedly, AMB+LF treatment did not lead to increased expression of iron or zinc homeostasis genes however we observed decreased expression of oxidative stress response genes. Addition of iron or zinc to AMB+LF treated cells did not rescue the synergy, supporting the likelihood that the mechanism of synergy involves more than iron and zinc chelation. We clustered genes based on patterns of co-expression and found by network analysis that many genes involved in iron and zinc homeostasis, which have dysregulated expression upon AMB+LF treatment, are targets of transcription factors Aft1p and Zap1p. Hypothesizing that these might play a key role in the synergistic response, knock-out mutants of Aft1 and Zap1 were tested for increased sensitivity to AMB and oxidative stress. Both mutants showed hypersensitivity towards these treatments. Our results suggest the mechanism of AMB+LF synergy involves disruption to oxidative stress response, in addition to chelation of iron and zinc. Since Zap1 is conserved in C. neoformans and contains a putative drug binding domain, we suggest novel Zap1 binding molecules could be combined with existing antifungals to serve as synergistic antifungal treatments for this species.
2016-12-04 | GSE80357 | GEO