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In vivo bioluminescence imaging of labile iron accumulation in a murine model of infection.
Aron AT, Heffern MC, Lonergan ZR, Vander Wal MN, Blank BR, Spangler B, Zhang Y, Park HM, Stahl A, Renslo AR, Skaar EP, Chang CJ
(2017) Proc Natl Acad Sci U S A 114: 12669-12674
MeSH Terms: 2,2'-Dipyridyl, Acinetobacter Infections, Acinetobacter baumannii, Anemia, Iron-Deficiency, Animals, Cation Transport Proteins, Cations, Divalent, Disease Models, Animal, Ferric Compounds, Firefly Luciferin, Fluorescent Dyes, Gene Expression Regulation, Hepcidins, Homeostasis, Iron, Iron Overload, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Luminescent Measurements, Mice, Mice, Transgenic, Quaternary Ammonium Compounds, Receptors, Transferrin, Signal Transduction, Transferrin
Show Abstract · Added March 15, 2018
Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release d-aminoluciferin for selective reactivity-based detection of Fe with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.
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25 MeSH Terms
Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality.
Wynn JL, Scumpia PO, Stocks BT, Romano-Keeler J, Alrifai MW, Liu JH, Kim AS, Alford CE, Matta P, Weitkamp JH, Moore DJ
(2015) J Immunol 195: 1064-70
MeSH Terms: Adoptive Transfer, Animals, Antibodies, Antigens, CD, Bone Marrow Cells, CD11b Antigen, Endotoxins, Erythroid Cells, Female, Fetal Blood, Humans, Male, Mice, Mice, Inbred C57BL, Receptors, Transferrin, Reticulocytes, Sepsis, Spleen
Show Abstract · Added June 24, 2015
Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization.
Copyright © 2015 by The American Association of Immunologists, Inc.
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18 MeSH Terms
Microtubule motors power plasma membrane tubulation in clathrin-independent endocytosis.
Day CA, Baetz NW, Copeland CA, Kraft LJ, Han B, Tiwari A, Drake KR, De Luca H, Chinnapen DJ, Davidson MW, Holmes RK, Jobling MG, Schroer TA, Lencer WI, Kenworthy AK
(2015) Traffic 16: 572-90
MeSH Terms: Animals, COS Cells, Cell Membrane, Chlorocebus aethiops, Cholera Toxin, Clathrin, Dyneins, Endocytosis, HeLa Cells, Humans, Microtubules, Protein Binding, Receptors, Transferrin
Show Abstract · Added February 12, 2016
How the plasma membrane is bent to accommodate clathrin-independent endocytosis remains uncertain. Recent studies suggest Shiga and cholera toxin induce membrane curvature required for their uptake into clathrin-independent carriers by binding and cross-linking multiple copies of their glycosphingolipid receptors on the plasma membrane. But it remains unclear if toxin-induced sphingolipid crosslinking provides sufficient mechanical force for deforming the plasma membrane, or if host cell factors also contribute to this process. To test this, we imaged the uptake of cholera toxin B-subunit into surface-derived tubular invaginations. We found that cholera toxin mutants that bind to only one glycosphingolipid receptor accumulated in tubules, and that toxin binding was entirely dispensable for membrane tubulations to form. Unexpectedly, the driving force for tubule extension was supplied by the combination of microtubules, dynein and dynactin, thus defining a novel mechanism for generating membrane curvature during clathrin-independent endocytosis.
© 2015 The Authors. Traffic published by John Wiley & Sons Ltd.
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13 MeSH Terms
The sodium channel accessory subunit Navβ1 regulates neuronal excitability through modulation of repolarizing voltage-gated K⁺ channels.
Marionneau C, Carrasquillo Y, Norris AJ, Townsend RR, Isom LL, Link AJ, Nerbonne JM
(2012) J Neurosci 32: 5716-27
MeSH Terms: Analysis of Variance, Animals, Bacterial Proteins, Biophysics, Biotinylation, Cell Line, Transformed, Cerebral Cortex, Cycloheximide, Electric Stimulation, Endocytosis, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Immunoprecipitation, Luminescent Proteins, Mass Spectrometry, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Patch-Clamp Techniques, Protein Synthesis Inhibitors, Proteomics, RNA, Small Interfering, Receptors, Transferrin, Shal Potassium Channels, Sodium Channels, Transfection, Voltage-Gated Sodium Channel beta-1 Subunit
Show Abstract · Added February 20, 2015
The channel pore-forming α subunit Kv4.2 is a major constituent of A-type (I(A)) potassium currents and a key regulator of neuronal membrane excitability. Multiple mechanisms regulate the properties, subcellular targeting, and cell-surface expression of Kv4.2-encoded channels. In the present study, shotgun proteomic analyses of immunoprecipitated mouse brain Kv4.2 channel complexes unexpectedly identified the voltage-gated Na⁺ channel accessory subunit Navβ1. Voltage-clamp and current-clamp recordings revealed that knockdown of Navβ1 decreases I(A) densities in isolated cortical neurons and that action potential waveforms are prolonged and repetitive firing is increased in Scn1b-null cortical pyramidal neurons lacking Navβ1. Biochemical and voltage-clamp experiments further demonstrated that Navβ1 interacts with and increases the stability of the heterologously expressed Kv4.2 protein, resulting in greater total and cell-surface Kv4.2 protein expression and in larger Kv4.2-encoded current densities. Together, the results presented here identify Navβ1 as a component of native neuronal Kv4.2-encoded I(A) channel complexes and a novel regulator of I(A) channel densities and neuronal excitability.
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29 MeSH Terms
Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface.
Tan S, Noto JM, Romero-Gallo J, Peek RM, Amieva MR
(2011) PLoS Pathog 7: e1002050
MeSH Terms: Adaptation, Physiological, Animals, Antigens, Bacterial, Bacterial Adhesion, Bacterial Proteins, Caco-2 Cells, Cell Line, Cell Membrane, Cell Polarity, Dogs, Down-Regulation, Epithelium, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Intercellular Junctions, Iron, Receptors, Transferrin, Sequence Deletion, Signal Transduction, Transcytosis, Transferrin
Show Abstract · Added March 5, 2014
Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche.
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2 Members
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24 MeSH Terms
D-AKAP2 interacts with Rab4 and Rab11 through its RGS domains and regulates transferrin receptor recycling.
Eggers CT, Schafer JC, Goldenring JR, Taylor SS
(2009) J Biol Chem 284: 32869-80
MeSH Terms: A Kinase Anchor Proteins, Cell Line, Cytosol, Endocytosis, Endosomes, Flow Cytometry, HeLa Cells, Humans, Protein Structure, Tertiary, RNA Interference, Receptors, Transferrin, Transferrin, rab GTP-Binding Proteins, rab4 GTP-Binding Proteins
Show Abstract · Added January 20, 2015
Dual-specific A-kinase-anchoring protein 2 (D-AKAP2/AKAP10), which interacts at its carboxyl terminus with protein kinase A and PDZ domain proteins, contains two tandem regulator of G-protein signaling (RGS) domains for which the binding partners have remained unknown. We show here that these RGS domains interact with Rab11 and GTP-bound Rab4, the first demonstration of RGS domains binding small GTPases. Rab4 and Rab11 help regulate membrane trafficking through the endocytic recycling pathways by recruiting effector proteins to specific membrane domains. Although D-AKAP2 is primarily cytosolic in HeLa cells, a fraction of the protein localizes to endosomes and can be recruited there to a greater extent by overexpression of Rab4 or Rab11. D-AKAP2 also regulates the morphology of the Rab11-containing compartment, with co-expression causing accumulation of both proteins on enlarged endosomes. Knockdown of D-AKAP2 by RNA interference caused a redistribution of both Rab11 and the constitutively recycling transferrin receptor to the periphery of cells. Knockdown also caused an increase in the rate of transferrin recycling, suggesting that D-AKAP2 promotes accumulation of recycling proteins in the Rab4/Rab11-positive endocytic recycling compartment.
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14 MeSH Terms
RhoB plays an essential role in CXCR2 sorting decisions.
Neel NF, Lapierre LA, Goldenring JR, Richmond A
(2007) J Cell Sci 120: 1559-71
MeSH Terms: Actins, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Chemotaxis, Cycloheximide, Cytochalasin B, Endosomes, Guanosine Triphosphate, Humans, Interleukin-8, Lysosome-Associated Membrane Glycoproteins, Lysosomes, Models, Biological, Mutation, Protein Transport, RNA, Small Interfering, Receptor, IGF Type 2, Receptors, Interleukin-8B, Receptors, Transferrin, Thiazolidines, Transfection, rab GTP-Binding Proteins, rab4 GTP-Binding Proteins, rhoB GTP-Binding Protein
Show Abstract · Added May 30, 2013
The CXCR2 chemokine receptor is a G-protein-coupled receptor that undergoes clathrin-mediated endocytosis upon ligand binding. The trafficking of CXCR2 is crucial for cells to maintain a proper chemotactic response. The mechanisms that regulate the recycling/degradation sorting decision are unknown. In this study, we used dominant-negative (T19N) and GTPase-deficient activated (Q63L) RhoB mutants, as well as RhoB small interfering RNA (siRNA) to investigate the role of RhoB in CXCR2 trafficking. Expression of either of the RhoB mutants or transfection of RhoB siRNA impaired CXCR2-mediated chemotaxis. Expression of RhoB T19N and transfection of RhoB siRNA impaired sorting of CXCR2 to the lysosome after 3 hours of CXCL8 stimulation and impaired CXCL8-induced CXCR2 degradation. In cells expressing the RhoB Q63L mutant, CXCR2 recycling through the Rab11a recycling compartment was impaired after 30 minutes of CXCL8 stimulation as was CXCL8-induced CXCR2 degradation. For cells expressing activated RhoB, CXCR2 colocalized with Rab4, a marker for the rapid recycling pathway, and with the mannose-6-phosphate receptor, which traffics between the trans-Golgi network and endosomes. These data suggest that CXCR2 recycles through alternative pathways. We conclude that oscillation of RhoB GTPase activity is essential for appropriate sorting decisions, and for directing CXCR2 degradation and recycling--events that are required for optimal chemotaxis.
2 Communities
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24 MeSH Terms
Role of protein kinase C betaII in influenza virus entry via late endosomes.
Sieczkarski SB, Brown HA, Whittaker GR
(2003) J Virol 77: 460-9
MeSH Terms: Biological Transport, Endosomes, Epidermal Growth Factor, ErbB Receptors, HeLa Cells, Humans, Hydrogen-Ion Concentration, Influenza A virus, Isoenzymes, Protein Kinase C, Protein Kinase C beta, Receptors, Transferrin, Semliki forest virus, Transfection
Show Abstract · Added March 21, 2013
Many viruses take advantage of receptor-mediated endocytosis in order to enter target cells. We have utilized influenza virus and Semliki Forest virus (SFV) to define a role for protein kinase C betaII (PKCbetaII) in endocytic trafficking. We show that specific PKC inhibitors prevent influenza virus infection, suggesting a role for classical isoforms of PKC. We also examined virus entry in cells overexpressing dominant-negative forms of PKCalpha and -beta. Cells expressing a phosphorylation-deficient form of PKCbetaII (T500V), but not an equivalent mutant form of PKCalpha, inhibited successful influenza virus entry-with the virus accumulating in late endosomes. SFV, however, believed to enter cells from the early endosome, was unaffected by PKCbetaII T500V expression. We also examined the trafficking of two cellular ligands, transferrin and epidermal growth factor (EGF). PKCbetaII T500V expression specifically blocked EGF receptor trafficking and degradation, without affecting transferrin receptor recycling. As with influenza virus, in PKCbetaII kinase-dead cells, EGF receptor was trapped in a late endosome compartment. Our findings suggest that PKCbetaII is an important regulator of a late endosomal sorting event needed for influenza virus entry and infection.
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1 Members
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14 MeSH Terms
Efficient endocytosis of the cystic fibrosis transmembrane conductance regulator requires a tyrosine-based signal.
Prince LS, Peter K, Hatton SR, Zaliauskiene L, Cotlin LF, Clancy JP, Marchase RB, Collawn JF
(1999) J Biol Chem 274: 3602-9
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, COS Cells, Cystic Fibrosis Transmembrane Conductance Regulator, DNA Primers, Endocytosis, Molecular Sequence Data, Protein Sorting Signals, Receptors, Transferrin, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Tyrosine
Show Abstract · Added June 9, 2010
We previously demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR) is rapidly endocytosed in epithelial cells (Prince, L. S., Workman, R. B., Jr., and Marchase, R. B. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 5192-5196). To determine the structural features of CFTR required for endocytosis, we prepared chimeric molecules consisting of the amino-terminal (residues 2-78) and carboxyl-terminal tail regions (residues 1391-1476) of CFTR, each fused to the transmembrane and extracellular domains of the transferrin receptor. Functional analysis of the CFTR-(2-78) and CFTR-(1391-1476) indicated that both chimeras were rapidly internalized. Deletion of residues 1440-1476 had no effect on chimera internalization. Mutations of potential internalization signals in both cytoplasmic domains reveal that only one mutation inhibits internalization, Y1424A. Using a surface biotinylation reaction, we also examined internalization rates of wild type and mutant CFTRs expressed in COS-7 cells. We found that both wild type and A1440X CFTR were rapidly internalized, whereas the Y1424A CFTR mutant, like the chimeric protein, had approximately 40% reduced internalization activity. Deletions in the amino-terminal tail region of CFTR resulted in defective trafficking of CFTR out of the endoplasmic reticulum to the cell surface, suggesting that an intact amino terminus is critical for biosynthesis. In summary, our results suggest that both tail regions of CFTR are sufficient to promote rapid internalization of a reporter molecule and that tyrosine 1424 is required for efficient CFTR endocytosis.
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13 MeSH Terms
Maternal origin of transferrin receptor positive cells in venous blood of pregnant women.
Slunga-Tallberg A, el-Rifai W, Keinänen M, Ylinen K, Kurki T, Klinger K, Ylikorkala O, Larramendy ML, Knuutila S
(1996) Clin Genet 49: 196-9
MeSH Terms: Adult, Antibodies, Monoclonal, Antigens, CD, Antigens, Differentiation, B-Lymphocyte, Bone Marrow Cells, Chromosomes, Human, Erythrocytes, Female, Fetal Blood, Fetus, Genetic Techniques, Humans, In Situ Hybridization, Fluorescence, Male, Pregnancy, Receptors, Transferrin, X Chromosome, Y Chromosome
Show Abstract · Added March 5, 2014
We studied the origin of transferrin receptor (CD71) positive cells in blood from seven women pregnant with a male fetus in order to explore if fetal cells could be detected among them. We used a technique that allows direct chromosomal analysis by in situ hybridization on immunologically and morphologically classified cells. Enrichment was performed by magnetic activated cell sorting (miniMACS) using an anti-CD71 monoclonal antibody. The cells were immunophenotyped by alkaline phosphatase anti-alkaline phosphatase immunostaining with the same antibody. The origin of the immunophenotyped cells was studied by in situ hybridization using an X cosmid Y repeat chromosome specific probe cocktail. CD71 positive cells were found in six of the seven women at the range of 4 to 43 in respective samples. Over 90% of the CD71 positive cells were nucleated erythrocytes. None of the detected positive cells were shown to be fetal. Thus, the use of transferrin receptor antigen alone in combination with the miniMACS may not be sufficient for enrichment of fetal cells.
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18 MeSH Terms