scholarly journals Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans

2019 ◽  
Author(s):  
Naomi Shomer ◽  
Alexandre Zacharie Kadhim ◽  
Jennifer Margaret Grants ◽  
Xuanjin Cheng ◽  
Amy Fong-Yuk Poon ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Physiological Stress ◽  
Toxic Metal ◽  
Nuclear Hormone Receptor ◽  
Egg Laying ◽  
Metal Stress ◽  
Loss Of Function ◽  
Metal Detoxification ◽  
Excess Zinc

AbstractZinc is essential for cellular functions as it is a catalytic and structural component of many proteins. In contrast, cadmium is not required in biological systems and is toxic. Zinc and cadmium levels are closely monitored and regulated as their excess causes cell stress. To maintain homeostasis, organisms induce metal detoxification gene programs through stress responsive transcriptional regulatory complexes. In Caenorhabditis elegans, the MDT-15 subunit of the evolutionarily conserved Mediator transcriptional coregulator is required to induce genes upon exposure to excess zinc and cadmium. However, the regulatory partners of MDT-15 in this response, its role in cellular and physiological stress adaptation, and the putative role mammalian for MED15 in the metal stress responses remain unknown. Here, we show that MDT-15 interacts physically and functionally with the Nuclear Hormone Receptor HIZR-1 to promote molecular, cellular, and organismal adaptation to excess metals. Using gain- and loss-of-function mutants and qPCR and reporter analysis, we find that mdt-15 and hizr-1 cooperate to induce zinc and cadmium responsive genes. Moreover, the two proteins interact physically in yeast-two-hybrid assays and this interaction is enhanced by the addition of zinc or cadmium, the former a known ligand of HIZR-1. Functionally, mdt-15 and hizr-1 mutants show defective storage of excess zinc in the gut, and at the organismal level, mdt-15 mutants are hypersensitive to zinc- and cadmium-induced reductions in egg-laying. Lastly, mammalian MDT-15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a metal-stimulated fashion, and human MED15 is required to induce a metallothionein gene in lung adenocarcinoma cells exposed to cadmium. Collectively, our data show that mdt-15 and hizr-1 cooperate to regulate metal detoxification and zinc storage and that this mechanism appears to be at least partially conserved in mammals.

scholarly journals Mediator subunit MDT-15/MED15 and Nuclear Receptor HIZR-1/HNF4 cooperate to regulate toxic metal stress responses in Caenorhabditis elegans

PLoS Genetics ◽  
2019 ◽  
Vol 15 (12) ◽  
pp. e1008508 ◽  
Author(s):  
Naomi Shomer ◽  
Alexandre Zacharie Kadhim ◽  
Jennifer Margaret Grants ◽  
Xuanjin Cheng ◽  
Deema Alhusari ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Nuclear Receptor ◽  
Stress Responses ◽  
Toxic Metal ◽  
Metal Stress

scholarly journals Screening for Presenilin Inhibitors Using the Free-Living Nematode, Caenorhabditis elegans

2004 ◽  
Vol 9 (2) ◽  
pp. 147-152 ◽  
Author(s):  
Brenda R. Ellerbrock ◽  
Eileen M. Coscarelli ◽  
Mark E. Gurney ◽  
Timothy G. Geary
Keyword(s):  
Caenorhabditis Elegans ◽  
High Throughput Screening ◽  
Screening Method ◽  
Genetic System ◽  
Body Cavity ◽  
Egg Laying ◽  
The Body ◽  
Loss Of Function ◽  
C Elegans ◽  
Automated Method

Caenorhabditis elegans contains 3 homologs of presenilin genes that are associated with Alzheimer s disease. Loss-of-function mutations in C. elegans genes cause a defect in egg laying. In humans, loss of presenilin-1 (PS1) function reduces amyloid-beta peptide processing from the amyloid protein precursor. Worms were screened for compounds that block egg laying, phenocopying presenilin loss of function. To accommodate even relatively high throughput screening, a semi-automated method to quantify egg laying was devised by measuring the chitinase released into the culture medium. Chitinase is released by hatching eggs, but little is shed into the medium from the body cavity of a hermaphrodite with an egg laying deficient ( egl) phenotype. Assay validation involved measuring chitinase release from wild-type C. elegans (N2 strain), sel-12 presenilin loss-of-function mutants, and 2 strains of C. elegans with mutations in the egl-36K+ channel gene. Failure to find specific presenilin inhibitors in this collection likely reflects the small number of compounds tested, rather than a flaw in screening strategy. Absent defined biochemical pathways for presenilin, this screening method, which takes advantage of the genetic system available in C. elegans and its historical use for anthelminthic screening, permits an entry into mechanism-based discovery of drugs for Alzheimer s disease. ( Journal of Biomolecular Screening 2004:147-152)

scholarly journals Heavy metal sensitivities of gene deletion strains for ITT1 and RPS1A connect their activities to the expression of URE2, a key gene involved in metal detoxification in yeast

2018 ◽  
Author(s):  
Houman Moteshareie ◽  
Maryam Hajikarimlou ◽  
Alex Mulet Indrayanti ◽  
Daniel Burnside ◽  
Ana Paula Dias ◽  
...  
Keyword(s):  
Heavy Metal ◽  
Molecular Mechanisms ◽  
Gene Deletion ◽  
Toxic Metal ◽  
Metal Stress ◽  
Yeast Cells ◽  
Metal Detoxification ◽  
Wide Range ◽  
Glutathione S Transferases ◽  
Yeast Genes

AbstractHeavy metal and metalloid contaminations are among the most concerning types of pollutant in the environment. Consequently, it is important to investigate the molecular mechanisms of cellular responses and detoxification pathways for these compounds in living organisms. To date, a number of genes have been linked to the detoxification process. The expression of these genes can be controlled at both transcriptional and translational levels. In baker’s yeast, Saccharomyces cerevisiae, resistance to a wide range of toxic metals is regulated by glutathione S-transferases. Yeast URE2 encodes for a protein that has glutathione peroxidase activity and is homologous to mammalian glutathione S-transferases. The URE2 expression is critical to cell survival under heavy metal stress. Here, we report on the finding of two genes, ITT1, an inhibitor of translation termination, and RPS1A, a small ribosomal protein, that when deleted yeast cells exhibit similar metal sensitivity phenotypes to gene deletion strain for URE2. Neither of these genes were previously linked to metal toxicity. Our gene expression analysis illustrates that these two genes affect URE2 mRNA expression at the level of translation.Summary statementWe identified two yeast genes, ITT1 and RPS1A, that when deleted, results in yeast cells sensitivity to heavy metals and metalloids. Further investigation indicated that they influence the expression of URE2 gene, a key player in metal detoxification, by upregulating its translation. Our findings suggest that ITT1 and RPS1A play an indirect role in responding to toxic metal stress.

scholarly journals Analysis of dominant mutations affecting muscle excitation in Caenorhabditis elegans.

Genetics ◽  
1995 ◽  
Vol 141 (3) ◽  
pp. 961-976 ◽  
Author(s):  
D J Reiner ◽  
D Weinshenker ◽  
J H Thomas
Keyword(s):  
Caenorhabditis Elegans ◽  
Muscle Activation ◽  
Gene Mutations ◽  
Egg Laying ◽  
Loss Of Function ◽  
Laser Microbeam ◽  
New Genes ◽  
Wild Type Phenotype ◽  
Apparent Loss ◽  
Muscle Types

Abstract We examined mutations that disrupt muscle activation in Caenorhabditis elegans. Fifteen of 17 of these genes were identified previously and we describe new mutations in three of them. We also describe mutations in two new genes, exp-3 and exp-4. We assessed the degree of defect in pharyngeal, body-wall, egg-laying, and enteric muscle activation in animals mutant for each gene. Mutations in all 17 genes are semidominant and, in cases that could be tested, appear to be gain-of-function. Based on their phenotypes, the genes fall into three broad categories: mutations in 11 genes cause defective muscle activation, mutations in four genes cause hyperactivated muscle, and mutations in two genes cause defective activation in some muscle types and hyperactivation in others. In all testable cases, the mutations blocked response to pharmacological activators of egg laying, but did not block muscle activation by irradiation with a laser microbeam. The data suggest that these mutations affect muscle excitation, but not the capacity of the muscle fibers to contract. For most of the genes, apparent loss-of-function mutants have a grossly wild-type phenotype. These observations suggest that there is a large group of genes that function in muscle excitation that can be identified primarily by dominant mutations.

scholarly journals The G-Protein β-Subunit GPB-2 in Caenorhabditis elegans Regulates the Goα-Gqα Signaling Network Through Interactions With the Regulator of G-Protein Signaling Proteins EGL-10 and EAT-16

Genetics ◽  
2001 ◽  
Vol 158 (1) ◽  
pp. 221-235 ◽  
Author(s):  
Alexander M van der Linden ◽  
Femke Simmer ◽  
Edwin Cuppen ◽  
Ronald H A Plasterk
Keyword(s):  
Caenorhabditis Elegans ◽  
G Protein ◽  
Essential Gene ◽  
Specific Interaction ◽  
Egg Laying ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Β Subunit ◽  
Loss Of Function ◽  
Pharyngeal Pumping

Abstract The genome of Caenorhabditis elegans harbors two genes for G-protein β-subunits. Here, we describe the characterization of the second G-protein β-subunit gene gpb-2. In contrast to gpb-1, gpb-2 is not an essential gene even though, like gpb-1, gpb-2 is expressed during development, in the nervous system, and in muscle cells. A loss-of-function mutation in gpb-2 produces a variety of behavioral defects, including delayed egg laying and reduced pharyngeal pumping. Genetic analysis shows that GPB-2 interacts with the GOA-1 (homologue of mammalian Goα) and EGL-30 (homologue of mammalian Gqα) signaling pathways. GPB-2 is most similar to the divergent mammalian Gβ5 subunit, which has been shown to mediate a specific interaction with a Gγ-subunit-like (GGL) domain of RGS proteins. We show here that GPB-2 physically and genetically interacts with the GGL-containing RGS proteins EGL-10 and EAT-16. Taken together, our results suggest that GPB-2 works in concert with the RGS proteins EGL-10 and EAT-16 to regulate GOA-1 (Goα) and EGL-30 (Gqα) signaling.

Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans.

Genetics ◽  
1993 ◽  
Vol 135 (3) ◽  
pp. 765-783 ◽  
Author(s):  
M Sundaram ◽  
I Greenwald
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Gene Dosage ◽  
Egg Laying ◽  
Loss Of Function ◽  
Cell Fate Decision ◽  
Cell Fates ◽  
Cell Fate Decisions ◽  
Suppressor Mutations ◽  
Fate Decision

Abstract The lin-12 gene of Caenorhabditis elegans is thought to encode a receptor which mediates cell-cell interactions required to specify certain cell fates. Reversion of the egg-laying defective phenotype caused by a hypomorphic lin-12 allele identified rare extragenic suppressor mutations in five genes, sel-1, sel-9, sel-10, sel-11 and sel(ar40) (sel = suppressor and/or enhancer of lin-12). Mutations in each of these sel genes suppress defects associated with reduced lin-12 activity, and enhance at least one defect associated with elevated lin-12 activity. None of the sel mutations cause any obvious phenotype in a wild-type background. Gene dosage experiments suggest that sel-1 and sel(ar40) mutations are reduction-of-function mutations, while sel-9 and sel-11 mutations are gain-of-function mutations. sel-1, sel-9, sel-11 and sel(ar40) mutations do not suppress amorphic lin-12 alleles, while sel-10 mutations are able to bypass partially the requirement for lin-12 activity in at least one cell fate decision. sel-1, sel-9, sel-10, sel-11 and sel(ar40) mutations are also able to suppress the maternal-effect lethality caused by a partial loss-of-function allele of glp-1, a gene that is both structurally and functionally related to lin-12. These sel genes may therefore function in both lin-12 and glp-1 mediated cell fate decisions.

scholarly journals Identification of a Novel Link between the Intermediate Filament Organizer IFO-1 and Cholesterol Metabolism in the Caenorhabditis elegans Intestine

2020 ◽  
Vol 21 (21) ◽  
pp. 8219
Author(s):  
Richard A. Coch ◽  
Florian Geisler ◽  
Andrea Annibal ◽  
Adam Antebi ◽  
Rudolf E. Leube
Keyword(s):  
Caenorhabditis Elegans ◽  
Intermediate Filament ◽  
Cholesterol Metabolism ◽  
Nuclear Hormone Receptor ◽  
Intestinal Lumen ◽  
Apical Plasma Membrane ◽  
Cholesterol Depletion ◽  
Loss Of Function ◽  
Reduced Body ◽  
Filament Network

The intestine is an organ essential to organismal nutrient absorption, metabolic control, barrier function and immunoprotection. The Caenorhabditis elegans intestine consists of 20 cells harboring a dense intermediate filament network positioned below the apical plasma membrane that forms a junction-anchored sheath around the intestinal lumen. This evolutionarily conserved arrangement provides mechanical and overall stress-protection, and it serves as an important model for deciphering the role of intestinal architecture in metazoan biology. We recently reported that the loss-of-function mutation of the intestinal intermediate filament organizer IFO-1 perturbs this architecture, leading to reduced body size and reproduction. Here, we demonstrate that the IFO-1 mutation dramatically affects cholesterol metabolism. Mutants showed an increased sensitivity to cholesterol depletion, reduced cholesterol uptake, and cholesterol transfer to the gonads, which is also observed in worms completely lacking an intermediate filament network. Accordingly, we found striking similarities to transcriptome and lipidome profiles of a nuclear hormone receptor (NHR)-8 mutant. NHR-8 is homologous to mammalian LXR (liver X receptor) that serves as a sterol sensor and transcriptional regulator of lipid metabolism. Remarkably, increasing exogenous cholesterol partially rescues the developmental retardation in IFO-1 mutants. Our results uncover a novel link of the intestinal intermediate filament cytoskeleton to cholesterol metabolism that contributes to compromised growth and reproduction.

scholarly journals Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans

2021 ◽  
Vol 22 (9) ◽  
pp. 4363
Author(s):  
Rajesh Kumar ◽  
Andreas S. Reichert
Keyword(s):  
Stress Responses ◽  
Mammalian Cells ◽  
Physiological Stress ◽  
Yeast Cells ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Independent Manner ◽  
Common View ◽  
Atp Production ◽  
Atg Proteins

Mitochondria are double membrane-bound organelles in eukaryotic cells essential to a variety of cellular functions including energy conversion and ATP production, iron-sulfur biogenesis, lipid and amino acid metabolism, and regulating apoptosis and stress responses. Mitochondrial dysfunction is mechanistically linked to several neurodegenerative diseases, cancer, and ageing. Excessive and dysfunctional/damaged mitochondria are degraded by selective autophagic pathways known as mitophagy. Both budding yeast and mammals use the well-conserved machinery of core autophagy-related genes (ATGs) to execute and regulate mitophagy. In mammalian cells, the PINK1-PARKIN mitophagy pathway is a well-studied pathway that senses dysfunctional mitochondria and marks them for degradation in the lysosome. PINK1-PARKIN mediated mitophagy relies on ubiquitin-binding mitophagy adaptors that are non-ATG proteins. Loss-of-function mutations in PINK1 and PARKIN are linked to Parkinson´s disease (PD) in humans, and defective mitophagy is proposed to be a main pathomechanism. Despite the common view that yeast cells lack PINK1- and PARKIN-homologs and that mitophagy in yeast is solely regulated by receptor-mediated mitophagy, some studies suggest that a ubiquitination-dependent mitophagy pathway also exists. Here, we will discuss shared mechanisms between mammals and yeast, how mitophagy in the latter is regulated in a ubiquitin-dependent and -independent manner, and why these pathways are essential for yeast cell survival and fitness under various physiological stress conditions.

Emotions and health: The impact of emotions, emotions regulation, music, and acculturation on health

2008 ◽  
Vol 16 (3) ◽  
pp. 112-115 ◽  
Author(s):  
Stephan Bongard ◽  
Volker Hodapp ◽  
Sonja Rohrmann
Keyword(s):  
Stress Responses ◽  
Physiological Stress ◽  
Anger Expression ◽  
Domain Specific ◽  
Cardiovascular Stress ◽  
Expression Behavior ◽  
Cardio Vascular ◽  
And Coping ◽  
Relationship Of ◽  
The Impact

Abstract. Our unit investigates the relationship of emotional processes (experience, expression, and coping), their physiological correlates and possible health outcomes. We study domain specific anger expression behavior and associated cardio-vascular loads and found e.g. that particularly an open anger expression at work is associated with greater blood pressure. Furthermore, we demonstrated that women may be predisposed for the development of certain mental disorders because of their higher disgust sensitivity. We also pointed out that the suppression of negative emotions leads to increased physiological stress responses which results in a higher risk for cardiovascular diseases. We could show that relaxation as well as music activity like singing in a choir causes increases in the local immune parameter immunoglobuline A. Finally, we are investigating connections between migrants’ strategy of acculturation and health and found e.g. elevated cardiovascular stress responses in migrants when they where highly adapted to the German culture.

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