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Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity.
LaFrance ME, Farrow MA, Chandrasekaran R, Sheng J, Rubin DH, Lacy DB
(2015) Proc Natl Acad Sci U S A 112: 7073-8
MeSH Terms: Analysis of Variance, Antibodies, Monoclonal, Bacterial Proteins, Bacterial Toxins, Caco-2 Cells, Cell Adhesion Molecules, Clostridium difficile, Colon, Enterotoxins, Epithelial Cells, Genetic Complementation Test, HeLa Cells, Humans, Mutagenesis, Insertional, Nectins
Show Abstract · Added September 28, 2015
Clostridium difficile is the leading cause of hospital-acquired diarrhea in the United States. The two main virulence factors of C. difficile are the large toxins, TcdA and TcdB, which enter colonic epithelial cells and cause fluid secretion, inflammation, and cell death. Using a gene-trap insertional mutagenesis screen, we identified poliovirus receptor-like 3 (PVRL3) as a cellular factor necessary for TcdB-mediated cytotoxicity. Disruption of PVRL3 expression by gene-trap mutagenesis, shRNA, or CRISPR/Cas9 mutagenesis resulted in resistance of cells to TcdB. Complementation of the gene-trap or CRISPR mutants with PVRL3 resulted in restoration of TcdB-mediated cell death. Purified PVRL3 ectodomain bound to TcdB by pull-down. Pretreatment of cells with a monoclonal antibody against PVRL3 or prebinding TcdB to PVRL3 ectodomain also inhibited cytotoxicity in cell culture. The receptor is highly expressed on the surface epithelium of the human colon and was observed to colocalize with TcdB in both an explant model and in tissue from a patient with pseudomembranous colitis. These data suggest PVRL3 is a physiologically relevant binding partner that can serve as a target for the prevention of TcdB-induced cytotoxicity in C. difficile infection.
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15 MeSH Terms
Antennal-expressed ammonium transporters in the malaria vector mosquito Anopheles gambiae.
Pitts RJ, Derryberry SL, Pulous FE, Zwiebel LJ
(2014) PLoS One 9: e111858
MeSH Terms: Animals, Anopheles, Arthropod Antennae, Cation Transport Proteins, Genes, Insect, Genetic Complementation Test, Injections, Insect Proteins, Insect Vectors, Ion Channel Gating, Malaria, Mutation, Oocytes, Phylogeny, Protein Structure, Tertiary, RNA, Messenger, Saccharomyces cerevisiae, Xenopus
Show Abstract · Added February 19, 2015
The principal Afrotropical malaria vector mosquito, Anopheles gambiae remains a significant threat to human health. In this anthropophagic species, females detect and respond to a range of human-derived volatile kairomones such as ammonia, lactic acid, and other carboxylic acids in their quest for blood meals. While the molecular underpinnings of mosquito olfaction and host seeking are becoming better understood, many questions remain unanswered. In this study, we have identified and characterized two candidate ammonium transporter genes, AgAmt and AgRh50 that are expressed in the mosquito antenna and may contribute to physiological and behavioral responses to ammonia, which is an important host kairomone for vector mosquitoes. AgAmt transcripts are highly enhanced in female antennae while a splice variant of AgRh50 appears to be antennal-specific. Functional expression of AgAmt in Xenopus laevis oocytes facilitates inward currents in response to both ammonium and methylammonium, while AgRh50 is able to partially complement a yeast ammonium transporter mutant strain, validating their conserved roles as ammonium transporters. We present evidence to suggest that both AgAmt and AgRh50 are in vivo ammonium transporters that are important for ammonia sensitivity in An. gambiae antennae, either by clearing ammonia from the sensillar lymph or by facilitating sensory neuron responses to environmental exposure. Accordingly, AgAmt and AgRh50 represent new and potentially important targets for the development of novel vector control strategies.
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18 MeSH Terms
Genes required for assembly of pili associated with the Helicobacter pylori cag type IV secretion system.
Johnson EM, Gaddy JA, Voss BJ, Hennig EE, Cover TL
(2014) Infect Immun 82: 3457-70
MeSH Terms: Bacterial Proteins, Bacterial Secretion Systems, Cell Line, Epithelial Cells, Fimbriae, Bacterial, Gene Knockout Techniques, Genes, Bacterial, Genetic Complementation Test, Genomic Islands, Helicobacter pylori, Humans, Multiprotein Complexes, Protein Multimerization
Show Abstract · Added July 2, 2014
Helicobacter pylori causes numerous alterations in gastric epithelial cells through processes that are dependent on activity of the cag type IV secretion system (T4SS). Filamentous structures termed "pili" have been visualized at the interface between H. pylori and gastric epithelial cells, and previous studies suggested that pilus formation is dependent on the presence of the cag pathogenicity island (PAI). Thus far, there has been relatively little effort to identify specific genes that are required for pilus formation, and the role of pili in T4SS function is unclear. In this study, we selected 7 genes in the cag PAI that are known to be required for T4SS function and investigated whether these genes were required for pilus formation. cagT, cagX, cagV, cagM, and cag3 mutants were defective in both T4SS function and pilus formation; complemented mutants regained T4SS function and the capacity for pilus formation. cagY and cagC mutants were defective in T4SS function but retained the capacity for pilus formation. These results define a set of cag PAI genes that are required for both pilus biogenesis and T4SS function and reveal that these processes can be uncoupled in specific mutant strains.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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13 MeSH Terms
Interplay between base excision repair activity and toxicity of 3-methyladenine DNA glycosylases in an E. coli complementation system.
Troll CJ, Adhikary S, Cueff M, Mitra I, Eichman BF, Camps M
(2014) Mutat Res 763-764: 64-73
MeSH Terms: Alkylation, DNA Glycosylases, DNA Repair, Escherichia coli, Genetic Complementation Test, Mutation, Saccharomyces cerevisiae, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added May 27, 2014
DNA glycosylases carry out the first step of base excision repair by removing damaged bases from DNA. The N3-methyladenine (3MeA) DNA glycosylases specialize in alkylation repair and are either constitutively expressed or induced by exposure to alkylating agents. To study the functional and evolutionary significance of constitutive versus inducible expression, we expressed two closely related yeast 3MeA DNA glycosylases - inducible Saccharomyces cerevisiae MAG and constitutive S. pombe Mag1 - in a glycosylase-deficient Escherichia coli strain. In both cases, constitutive expression conferred resistance to alkylating agent exposure. However, in the absence of exogenous alkylation, high levels of expression of both glycosylases were deleterious. We attribute this toxicity to excessive glycosylase activity, since suppressing spMag1 expression correlated with improved growth in liquid culture, and spMag1 mutants exhibiting decreased glycosylase activity showed improved growth and viability. Selection of a random spMag1 mutant library for increased survival in the presence of exogenous alkylation resulted in the selection of hypomorphic mutants, providing evidence for the presence of a genetic barrier to the evolution of enhanced glycosylase activity when constitutively expressed. We also show that low levels of 3MeA glycosylase expression improve fitness in our glycosylase-deficient host, implying that 3MeA glycosylase activity is likely necessary for repair of endogenous lesions. These findings suggest that 3MeA glycosylase activity is evolutionarily conserved for repair of endogenously produced alkyl lesions, and that inducible expression represents a common strategy to rectify deleterious effects of excessive 3MeA activity in the absence of exogenous alkylation challenge.
Copyright © 2014 Elsevier B.V. All rights reserved.
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9 MeSH Terms
Two Arabidopsis loci encode novel eukaryotic initiation factor 4E isoforms that are functionally distinct from the conserved plant eukaryotic initiation factor 4E.
Patrick RM, Mayberry LK, Choy G, Woodard LE, Liu JS, White A, Mullen RA, Tanavin TM, Latz CA, Browning KS
(2014) Plant Physiol 164: 1820-30
MeSH Terms: Amino Acid Sequence, Arabidopsis, Arabidopsis Proteins, Biological Assay, Computer Simulation, Conserved Sequence, Electrophoresis, Polyacrylamide Gel, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factor-4G, Genetic Complementation Test, Genetic Loci, Guanosine, Molecular Sequence Data, Phylogeny, Protein Binding, Protein Biosynthesis, Protein Isoforms, Saccharomyces cerevisiae, Self-Fertilization
Show Abstract · Added December 8, 2017
Canonical translation initiation in eukaryotes begins with the Eukaryotic Initiation Factor 4F (eIF4F) complex, made up of eIF4E, which recognizes the 7-methylguanosine cap of messenger RNA, and eIF4G, which serves as a scaffold to recruit other translation initiation factors that ultimately assemble the 80S ribosome. Many eukaryotes have secondary EIF4E genes with divergent properties. The model plant Arabidopsis (Arabidopsis thaliana) encodes two such genes in tandem loci on chromosome 1, EIF4E1B (At1g29550) and EIF4E1C (At1g29590). This work identifies EIF4E1B/EIF4E1C-type genes as a Brassicaceae-specific diverged form of EIF4E. There is little evidence for EIF4E1C gene expression; however, the EIF4E1B gene appears to be expressed at low levels in most tissues, though microarray and RNA Sequencing data support enrichment in reproductive tissue. Purified recombinant eIF4E1b and eIF4E1c proteins retain cap-binding ability and form functional complexes in vitro with eIF4G. The eIF4E1b/eIF4E1c-type proteins support translation in yeast (Saccharomyces cerevisiae) but promote translation initiation in vitro at a lower rate compared with eIF4E. Findings from surface plasmon resonance studies indicate that eIF4E1b and eIF4E1c are unlikely to bind eIF4G in vivo when in competition with eIF4E. This study concludes that eIF4E1b/eIF4E1c-type proteins, although bona fide cap-binding proteins, have divergent properties and, based on apparent limited tissue distribution in Arabidopsis, should be considered functionally distinct from the canonical plant eIF4E involved in translation initiation.
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19 MeSH Terms
Pif1 family helicases suppress genome instability at G-quadruplex motifs.
Paeschke K, Bochman ML, Garcia PD, Cejka P, Friedman KL, Kowalczykowski SC, Zakian VA
(2013) Nature 497: 458-62
MeSH Terms: Base Sequence, Conserved Sequence, DNA Damage, DNA Helicases, Epigenesis, Genetic, Evolution, Molecular, G-Quadruplexes, Gene Silencing, Genetic Complementation Test, Genomic Instability, Humans, Molecular Sequence Data, Mutation Rate, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Telomere Homeostasis
Show Abstract · Added March 7, 2014
The Saccharomyces cerevisiae Pif1 helicase is the prototypical member of the Pif1 DNA helicase family, which is conserved from bacteria to humans. Here we show that exceptionally potent G-quadruplex unwinding is conserved among Pif1 helicases. Moreover, Pif1 helicases from organisms separated by more than 3 billion years of evolution suppressed DNA damage at G-quadruplex motifs in yeast. The G-quadruplex-induced damage generated in the absence of Pif1 helicases led to new genetic and epigenetic changes. Furthermore, when expressed in yeast, human PIF1 suppressed both G-quadruplex-associated DNA damage and telomere lengthening.
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16 MeSH Terms
Human Asunder promotes dynein recruitment and centrosomal tethering to the nucleus at mitotic entry.
Jodoin JN, Shboul M, Sitaram P, Zein-Sabatto H, Reversade B, Lee E, Lee LA
(2012) Mol Biol Cell 23: 4713-24
MeSH Terms: 1-Alkyl-2-acetylglycerophosphocholine Esterase, Animals, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Nucleus, Centrosome, Chromosomal Proteins, Non-Histone, Drosophila melanogaster, Dyneins, Female, G2 Phase, Genetic Complementation Test, HEK293 Cells, HeLa Cells, Humans, Immunoblotting, Male, Mice, Microfilament Proteins, Microscopy, Fluorescence, Microtubule-Associated Proteins, Mitosis, Mutation, Nuclear Pore, Protein Binding, RNA Interference, Spindle Apparatus
Show Abstract · Added March 5, 2014
Recruitment of dynein motors to the nuclear surface is an essential step for nucleus-centrosome coupling in prophase. In cultured human cells, this dynein pool is anchored to nuclear pore complexes through RanBP2-Bicaudal D2 (BICD2) and Nup133- centromere protein F (CENP-F) networks. We previously reported that the asunder (asun) gene is required in Drosophila spermatocytes for perinuclear dynein localization and nucleus-centrosome coupling at G2/M of male meiosis. We show here that male germline expression of mammalian Asunder (ASUN) protein rescues asun flies, demonstrating evolutionary conservation of function. In cultured human cells, we find that ASUN down-regulation causes reduction of perinuclear dynein in prophase of mitosis. Additional defects after loss of ASUN include nucleus-centrosome uncoupling, abnormal spindles, and multinucleation. Coimmunoprecipitation and overlapping localization patterns of ASUN and lissencephaly 1 (LIS1), a dynein adaptor, suggest that ASUN interacts with dynein in the cytoplasm via LIS1. Our data indicate that ASUN controls dynein localization via a mechanism distinct from that of either BICD2 or CENP-F. We present a model in which ASUN promotes perinuclear enrichment of dynein at G2/M that facilitates BICD2- and CENP-F-mediated anchoring of dynein to nuclear pore complexes.
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28 MeSH Terms
Campylobacter jejuni type VI secretion system: roles in adaptation to deoxycholic acid, host cell adherence, invasion, and in vivo colonization.
Lertpiriyapong K, Gamazon ER, Feng Y, Park DS, Pang J, Botka G, Graffam ME, Ge Z, Fox JG
(2012) PLoS One 7: e42842
MeSH Terms: Agar, Animals, Bacterial Proteins, Bacterial Secretion Systems, Campylobacter Infections, Campylobacter jejuni, Cell Adhesion, Cell Proliferation, Deoxycholic Acid, Genes, Bacterial, Genetic Complementation Test, Hemolysin Proteins, Interleukin-10, Mice, Mice, Transgenic, Multigene Family, Mutation, Phenotype
Show Abstract · Added April 13, 2017
The recently identified type VI secretion system (T6SS) of proteobacteria has been shown to promote pathogenicity, competitive advantage over competing microorganisms, and adaptation to environmental perturbation. By detailed phenotypic characterization of loss-of-function mutants, in silico, in vitro and in vivo analyses, we provide evidence that the enteric pathogen, Campylobacter jejuni, possesses a functional T6SS and that the secretion system exerts pleiotropic effects on two crucial processes--survival in a bile salt, deoxycholic acid (DCA), and host cell adherence and invasion. The expression of T6SS during initial exposure to the upper range of physiological levels of DCA (0.075%-0.2%) was detrimental to C. jejuni proliferation, whereas down-regulation or inactivation of T6SS enabled C. jejuni to resist this effect. The C. jejuni multidrug efflux transporter gene, cmeA, was significantly up-regulated during the initial exposure to DCA in the wild type C. jejuni relative to the T6SS-deficient strains, suggesting that inhibition of proliferation is the consequence of T6SS-mediated DCA influx. A sequential modulation of the efflux transporter activity and the T6SS represents, in part, an adaptive mechanism for C. jejuni to overcome this inhibitory effect, thereby ensuring its survival. C. jejuni T6SS plays important roles in host cell adhesion and invasion as T6SS inactivation resulted in a reduction of adherence to and invasion of in vitro cell lines, while over-expression of a hemolysin co-regulated protein, which encodes a secreted T6SS component, greatly enhanced these processes. When inoculated into B6.129P2-IL-10(tm1Cgn) mice, the T6SS-deficient C. jejuni strains did not effectively establish persistent colonization, indicating that T6SS contributes to colonization in vivo. Taken together, our data demonstrate the importance of bacterial T6SS in host cell adhesion, invasion, colonization and, for the first time to our knowledge, adaptation to DCA, providing new insights into the role of T6SS in C. jejuni pathogenesis.
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18 MeSH Terms
Mtg16/Eto2 contributes to murine T-cell development.
Hunt A, Fischer M, Engel ME, Hiebert SW
(2011) Mol Cell Biol 31: 2544-51
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Bone Marrow Transplantation, Cell Lineage, Genetic Complementation Test, Lymphopoiesis, Mice, Mice, Mutant Strains, Nuclear Proteins, Protein Structure, Tertiary, Receptors, Notch, T-Lymphocytes, Transcription Factors
Show Abstract · Added November 4, 2012
Mtg16/Eto2 is a transcriptional corepressor that is disrupted by t(16;21) in acute myeloid leukemia. Using mice lacking Mtg16, we found that Mtg16 is a critical regulator of T-cell development. Deletion of Mtg16 led to reduced thymocyte development in vivo, and after competitive bone marrow transplantation, there was a nearly complete failure of Mtg16(-/-) cells to contribute to thymocyte development. This defect was recapitulated in vitro as Mtg16(-/-) Lineage(-)/Sca1(+)/c-Kit(+) (LSK) cells of the bone marrow or DN1 cells of the thymus failed to produce CD4(+)/CD8(+) cells in response to a Notch signal. Complementation of these defects by reexpressing Mtg16 showed that 3 highly conserved domains were somewhat dispensable for T-cell development but required the capacity of Mtg16 to suppress E2A-dependent transcriptional activation and to bind to the Notch intracellular domain. Thus, Mtg16 integrates the activities of signaling pathways and nuclear factors in the establishment of T-cell fate specification.
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13 MeSH Terms
The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy.
Long AA, Mahapatra CT, Woodruff EA, Rohrbough J, Leung HT, Shino S, An L, Doerge RW, Metzstein MM, Pak WL, Broadie K
(2010) J Cell Sci 123: 3303-15
MeSH Terms: Animals, Drosophila, Drosophila Proteins, Genetic Complementation Test, Genetic Testing, Light Signal Transduction, Morphogenesis, Neuromuscular Junction, Photoreceptor Cells, Invertebrate, Presynaptic Terminals, Protein-Serine-Threonine Kinases, Retina, Sequence Deletion, Synaptic Transmission, Synaptic Vesicles
Show Abstract · Added March 29, 2017
A systematic Drosophila forward genetic screen for photoreceptor synaptic transmission mutants identified no-on-and-no-off transient C (nonC) based on loss of retinal synaptic responses to light stimulation. The cloned gene encodes phosphatidylinositol-3-kinase-like kinase (PIKK) Smg1, a regulatory kinase of the nonsense-mediated decay (NMD) pathway. The Smg proteins act in an mRNA quality control surveillance mechanism to selectively degrade transcripts containing premature stop codons, thereby preventing the translation of truncated proteins with dominant-negative or deleterious gain-of-function activities. At the neuromuscular junction (NMJ) synapse, an extended allelic series of Smg1 mutants show impaired structural architecture, with decreased terminal arbor size, branching and synaptic bouton number. Functionally, loss of Smg1 results in a ~50% reduction in basal neurotransmission strength, as well as progressive transmission fatigue and greatly impaired synaptic vesicle recycling during high-frequency stimulation. Mutation of other NMD pathways genes (Upf2 and Smg6) similarly impairs neurotransmission and synaptic vesicle cycling. These findings suggest that the NMD pathway acts to regulate proper mRNA translation to safeguard synapse morphology and maintain the efficacy of synaptic function.
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15 MeSH Terms