scholarly journals Elucidating the H+ coupled Zn2+ transport mechanism of ZIP4; implications in Acrodermatitis Enteropathica

2018 ◽  
Author(s):  
Eitan Hoch ◽  
Israel Sekler
Keyword(s):  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Rare Condition ◽  
Transport Proteins ◽  
Fluorescent Imaging ◽  
Acrodermatitis Enteropathica ◽  
Extracellular Acidification ◽  
Mode Of Transport ◽  
Zip Transporters ◽  
In Cells

AbstractCellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely ZnTs (SLC30) that shuttle Zn2+ efflux, and ZIPs (SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3− or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3− failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis Enteropathica, a rare condition of Zn2+ deficiency.

scholarly journals Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica

2020 ◽  
Vol 21 (3) ◽  
pp. 734
Author(s):  
Eitan Hoch ◽  
Moshe Levy ◽  
Michal Hershfinkel ◽  
Israel Sekler
Keyword(s):  
Molecular Mechanisms ◽  
Rare Condition ◽  
Transport Proteins ◽  
Fluorescent Imaging ◽  
Zinc Transporters ◽  
Acrodermatitis Enteropathica ◽  
Extracellular Acidification ◽  
Mode Of Transport ◽  
Zip Transporters ◽  
In Cells

Cellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely zinc transporters (ZnTs; SLC30) that shuttle Zn2+ efflux, and ZRT-IRT-like proteins (ZIPs; SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3− or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3− failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis enteropathica, a rare condition of Zn2+ deficiency.

scholarly journals Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

2020 ◽  
Vol 31 (4) ◽  
pp. 799-816 ◽  
Author(s):  
Barbara Mara Klinkhammer ◽  
Sonja Djudjaj ◽  
Uta Kunter ◽  
Runolfur Palsson ◽  
Vidar Orn Edvardsson ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Molecular Mechanisms ◽  
Granulomatous Inflammation ◽  
Kidney Injury ◽  
Rare Condition ◽  
Therapeutic Interventions ◽  
Renal Tubules ◽  
Rodent Models ◽  
Adenine Phosphoribosyltransferase ◽  
Reparative Process

BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

scholarly journals miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Jin Zheng ◽  
Bo Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Renal Tubular Cell ◽  
In Cells

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

Role of membrane trafficking in plasma membrane solute transport

1994 ◽  
Vol 267 (1) ◽  
pp. C1-C24 ◽  
Author(s):  
N. A. Bradbury ◽  
R. J. Bridges
Keyword(s):  
Plasma Membrane ◽  
Solute Transport ◽  
Membrane Trafficking ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Water Channel ◽  
Transport Proteins ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulated Trafficking

Cells can rapidly and reversibly alter solute transport rates by changing the kinetics of transport proteins resident within the plasma membrane. Most notably, this can be brought about by reversible phosphorylation of the transporter. An additional mechanism for acute regulation of plasma membrane transport rates is by the regulated exocytic insertion of transport proteins from intracellular vesicles into the plasma membrane and their subsequent regulated endocytic retrieval. Over the past few years, the number of transporters undergoing this regulated trafficking has increased dramatically, such that what was once an interesting translocation of a few transporters has now become a widespread modality for regulating plasma membrane solute permeabilities. The aim of this article is to review the models proposed for the regulated trafficking of transport proteins and what lines of evidence should be obtained to document regulated exocytic insertion and endocytic retrieval of transport proteins. We highlight four transporters, the insulin-responsive glucose transporter, the antidiuretic hormone-responsive water channel, the urinary bladder H(+)-ATPase, and the cystic fibrosis transmembrane conductance regulator Cl- channel, and discuss the various approaches taken to document their regulated trafficking. Finally, we discuss areas of uncertainty that remain to be investigated concerning the molecular mechanisms involved in regulating the trafficking of proteins.

scholarly journals Clinics and genetic background of hereditary gingival fibromatosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Karolina Strzelec ◽  
Agata Dziedzic ◽  
Katarzyna Łazarz-Bartyzel ◽  
Aleksander M. Grabiec ◽  
Ewa Gutmajster ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rare Condition ◽  
Enrichment Score ◽  
Chromosome 2 ◽  
Chromosome 11 ◽  
Genetic Studies ◽  
Pathogenic Variants ◽  
Gingival Fibromatosis ◽  
Encoding Genes ◽  
Clinical Overview

Abstract Background Hereditary gingival fibromatosis (HGF) is a rare condition characterized by slowly progressive overgrowth of the gingiva. The severity of overgrowth may differ from mild causing phonetic and masticatory issues, to severe resulting in diastemas or malposition of teeth. Both, autosomal-dominant and autosomal-recessive forms of HGF are described. The aim of this review is a clinical overview, as well as a summary and discussion of the involvement of candidate chromosomal regions, pathogenic variants of genes, and candidate genes in the pathogenesis of HGF. The loci related to non-syndromic HGF have been identified on chromosome 2 (GINGF, GINGF3), chromosome 5 (GINGF2), chromosome 11 (GINGF4), and 4 (GINGF5). Of these loci, pathogenic variants of the SOS-1 and REST genes inducing HGF have been identified in the GINGF and the GINGF5, respectively. Furthermore, among the top 10 clusters of genes ranked by enrichment score, ATP binding, and fibronectin encoding genes were proposed as related to HGF. Conclusion The analysis of clinical reports as well as translational genetic studies published since the late’90s indicate the clinical and genetic heterogeneity of non-syndromic HGF and point out the importance of genetic studies and bioinformatics of more numerous unrelated families to identify novel pathogenic variants potentially inducing HGF. This strategy will help to unravel the molecular  mechanisms as well as uncover specific targets for novel and less invasive therapies of this rare, orphan condition.

scholarly journals The fog of genetics: Known unknowns and unknown unknowns in the genetics of complex traits and diseases

2019 ◽  
Author(s):  
João Pedro de Magalhães ◽  
Jingwei Wang
Keyword(s):  
Genetic Variability ◽  
Genetic Variants ◽  
Genetic Information ◽  
Complex Traits ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Genetic Associations ◽  
Missing Heritability ◽  
Genome Space ◽  
Known Unknowns

AbstractAssociating genetic variants with phenotypes is not only important to understand the underlying biology but also to identify potential drug targets for treating diseases. It is widely accepted that for most complex traits many associations remain to be discovered, the so-called “missing heritability.” Yet missing heritability can be estimated, it is a known unknown, and we argue is only a fraction of the unknowns in genetics. The majority of possible genetic variants in the genome space are either too rare to be detected or even entirely absent from populations, and therefore do not contribute to estimates of phenotypic or genetic variability. We call these unknown unknowns in genetics the “fog of genetics.” Using data from the 1000 Genomes Project we then show that larger genes with greater genetic diversity are more likely to be associated with human traits, demonstrating that genetic associations are biased towards particular types of genes and that the genetic information we are lacking about traits and diseases is potentially immense. Our results and model have multiple implications for how genetic variability is perceived to influence complex traits, provide insights on molecular mechanisms of disease and for drug discovery efforts based on genetic information.

P1-145: INFERRING THE MOLECULAR MECHANISMS OF NONCODING AD-ASSOCIATED GENETIC VARIANTS

2006 ◽  
Vol 14 (7S_Part_6) ◽  
pp. P331-P332
Author(s):  
Alexandre Amlie-Wolf ◽  
Mitchell Tang ◽  
Beth A. Dombroski ◽  
Jessica Way ◽  
Nikolaos Vrettos ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Molecular Mechanisms

scholarly journals The Influence of a Nanopatterned Scaffold that Mimics Abnormal Renal Mesangial Matrix on Mesangial Cell Behavior

2019 ◽  
Vol 20 (21) ◽  
pp. 5349
Author(s):  
Chia-Jung Chang ◽  
Rin Minei ◽  
Takeshi Sato ◽  
Akiyoshi Taniguchi
Keyword(s):  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Glomerular Disease ◽  
Cell Behavior ◽  
Type I ◽  
Mesangial Matrix ◽  
Cell Functions ◽  
In Cells

The alteration of mesangial matrix (MM) components in mesangium, such as type IV collagen (COL4) and type I collagen (COL1), is commonly found in progressive glomerular disease. Mesangial cells (MCs) responding to altered MM, show critical changes in cell function. This suggests that the diseased MM structure could play an important role in MC behavior. To investigate how MC behavior is influenced by the diseased MM 3D nanostructure, we fabricated the titanium dioxide (TiO2)-based nanopatterns that mimic diseased MM nanostructures. Immortalized mouse MCs were used to assess the influence of disease-mimic nanopatterns on cell functions, and were compared with a normal-mimic nanopattern. The results showed that the disease-mimic nanopattern induced disease-like behavior, including increased proliferation, excessive production of abnormal MM components (COL1 and fibronectin) and decreased normal MM components (COL4 and laminin α1). In contrast, the normal-mimic nanopattern actually resulted in cells displaying normal proliferation and the production of normal MM components. In addition, increased expressions of α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and integrin α5β1 were detected in cells grown on the disease-mimic nanopattern. These results indicated that the disease-mimic nanopattern induced disease-like cell behavior. These findings will help further establish a disease model that mimics abnormal MM nanostructures and also to elucidate the molecular mechanisms underlying glomerular disease.

scholarly journals Genomics of autism spectrum disorder: approach to therapy

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 627 ◽  
Author(s):  
Fatma Ayhan ◽  
Genevieve Konopka
Keyword(s):  
Autism Spectrum Disorder ◽  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Current Treatment ◽  
Spectrum Disorder ◽  
Current State ◽  
Genetics And Genomics

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition with no current treatment available. Although advances in genetics and genomics have identified hundreds of genes associated with ASD, very little is known about the pathophysiology of ASD and the functional contribution of specific genes to ASD phenotypes. Improved understanding of the biological function of ASD-associated genes and how this heterogeneous group of genetic variants leads to the disease is needed in order to develop therapeutic strategies. Here, we review the current state of ASD research related to gene discovery and examples of emerging molecular mechanisms (protein translation and alternative splicing). In addition, we discuss how patient-derived three-dimensional brain organoids might provide an opportunity to model specific genetic variants in order to define molecular and cellular defects that could be amenable for developing and screening personalized therapies related to ASD.

scholarly journals α5β1 integrin recycling promotes Arp2/3-independent cancer cell invasion via the formin FHOD3

2015 ◽  
Vol 210 (6) ◽  
pp. 1013-1031 ◽  
Author(s):  
Nikki R. Paul ◽  
Jennifer L. Allen ◽  
Anna Chapman ◽  
Maria Morlan-Mairal ◽  
Egor Zindy ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Cancer Cell Invasion ◽  
Coupling Protein ◽  
Α5β1 Integrin ◽  
In Cells

Invasive migration in 3D extracellular matrix (ECM) is crucial to cancer metastasis, yet little is known of the molecular mechanisms that drive reorganization of the cytoskeleton as cancer cells disseminate in vivo. 2D Rac-driven lamellipodial migration is well understood, but how these features apply to 3D migration is not clear. We find that lamellipodia-like protrusions and retrograde actin flow are indeed observed in cells moving in 3D ECM. However, Rab-coupling protein (RCP)-driven endocytic recycling of α5β1 integrin enhances invasive migration of cancer cells into fibronectin-rich 3D ECM, driven by RhoA and filopodial spike-based protrusions, not lamellipodia. Furthermore, we show that actin spike protrusions are Arp2/3-independent. Dynamic actin spike assembly in cells invading in vitro and in vivo is regulated by Formin homology-2 domain containing 3 (FHOD3), which is activated by RhoA/ROCK, establishing a novel mechanism through which the RCP–α5β1 pathway reprograms the actin cytoskeleton to promote invasive migration and local invasion in vivo.

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