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[PMID]:28961236
[Au] Autor:Brady LK; Wang H; Radens CM; Bi Y; Radovich M; Maity A; Ivan C; Ivan M; Barash Y; Koumenis C
[Ad] Endereço:Department of Radiation Oncology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
[Ti] Título:Transcriptome analysis of hypoxic cancer cells uncovers intron retention in EIF2B5 as a mechanism to inhibit translation.
[So] Source:PLoS Biol;15(9):e2002623, 2017 Sep.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cells adjust to hypoxic stress within the tumor microenvironment by downregulating energy-consuming processes including translation. To delineate mechanisms of cellular adaptation to hypoxia, we performed RNA-Seq of normoxic and hypoxic head and neck cancer cells. These data revealed a significant down regulation of genes known to regulate RNA processing and splicing. Exon-level analyses classified > 1,000 mRNAs as alternatively spliced under hypoxia and uncovered a unique retained intron (RI) in the master regulator of translation initiation, EIF2B5. Notably, this intron was expressed in solid tumors in a stage-dependent manner. We investigated the biological consequence of this RI and demonstrate that its inclusion creates a premature termination codon (PTC), that leads to a 65kDa truncated protein isoform that opposes full-length eIF2Bε to inhibit global translation. Furthermore, expression of 65kDa eIF2Bε led to increased survival of head and neck cancer cells under hypoxia, providing evidence that this isoform enables cells to adapt to conditions of low oxygen. Additional work to uncover -cis and -trans regulators of EIF2B5 splicing identified several factors that influence intron retention in EIF2B5: a weak splicing potential at the RI, hypoxia-induced expression and binding of the splicing factor SRSF3, and increased binding of total and phospho-Ser2 RNA polymerase II specifically at the intron retained under hypoxia. Altogether, these data reveal differential splicing as a previously uncharacterized mode of translational control under hypoxia and are supported by a model in which hypoxia-induced changes to cotranscriptional processing lead to selective retention of a PTC-containing intron in EIF2B5.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/genética
Perfilação da Expressão Gênica/métodos
Íntrons/genética
Biossíntese de Proteínas/genética
Hipóxia Tumoral/genética
[Mh] Termos MeSH secundário: Processamento Alternativo/genética
Sequência de Bases
Linhagem Celular Tumoral
Regulação Neoplásica da Expressão Gênica
Loci Gênicos
Neoplasias de Cabeça e Pescoço/genética
Neoplasias de Cabeça e Pescoço/patologia
Seres Humanos
Modelos Biológicos
Motivos de Nucleotídeos/genética
Fosforilação
Reação em Cadeia da Polimerase
Ligação Proteica
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
RNA Polimerase II/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Sequências Reguladoras de Ácido Nucleico/genética
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (EIF2B5 protein, human); 0 (Eukaryotic Initiation Factor-2B); 0 (Protein Isoforms); 0 (RNA, Messenger); EC 2.7.7.- (RNA Polymerase II)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2002623


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[PMID]:28306143
[Au] Autor:Raini G; Sharet R; Herrero M; Atzmon A; Shenoy A; Geiger T; Elroy-Stein O
[Ad] Endereço:Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
[Ti] Título:Mutant eIF2B leads to impaired mitochondrial oxidative phosphorylation in vanishing white matter disease.
[So] Source:J Neurochem;141(5):694-707, 2017 Jun.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Eukaryotic translation initiation factor 2B (eIF2B) is a master regulator of protein synthesis under normal and stress conditions. Mutations in any of the five genes encoding its subunits lead to vanishing white matter (VWM) disease, a recessive genetic deadly illness caused by progressive loss of white matter in the brain. In this study we used fibroblasts, which are not involved in the disease, to demonstrate the involvement of eIF2B in mitochondrial function and abundance. Mass spectrometry of total proteome of mouse embryonic fibroblasts (MEFs) isolated from Eif2b5 mice revealed unbalanced stoichiometry of proteins involved in oxidative phosphorylation and of mitochondrial translation machinery components, among others. Mutant MEFs exhibit 55% decrease in oxygen consumption rate per mtDNA content and 47% increase in mitochondrial abundance (p < 0.005), reflecting adaptation to energy requirements. A more robust eIF2B-associated oxidative respiration deficiency was found in mutant primary astrocytes, which exhibit > 3-fold lower ATP-linked respiration per cell despite a 2-fold increase in mtDNA content (p < 0.03). The 2-fold increase in basal and stimulated glycolysis in mutant astrocytes (p ≤ 0.03), but not in MEFs, demonstrates their higher energetic needs and further explicates their involvement in the disease. The data demonstrate the critical role of eIF2B in tight coordination of expression from nuclear and mitochondrial genomes and illuminates the importance of mitochondrial function in VWM pathology. Further dissection of the signaling network associated with eIF2B function will help generating therapeutic strategies for VWM disease and possibly other neurodegenerative disorders.
[Mh] Termos MeSH primário: Astrócitos/ultraestrutura
Fator de Iniciação 2B em Eucariotos/genética
Mitocôndrias/genética
Mutação/genética
Fosforilação Oxidativa
Consumo de Oxigênio/genética
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Antimicina A/farmacologia
Astrócitos/efeitos dos fármacos
Astrócitos/fisiologia
Carbonil Cianeto p-Trifluormetoxifenil Hidrazona/farmacologia
Ciclo Celular/efeitos dos fármacos
Ciclo Celular/genética
Tamanho Celular
Células Cultivadas
Cloranfenicol/farmacologia
Fator de Iniciação 2B em Eucariotos/metabolismo
Feminino
Fibroblastos/efeitos dos fármacos
Fibroblastos/imunologia
Fibroblastos/ultraestrutura
Antígenos de Histocompatibilidade/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Mitocôndrias/fisiologia
Fosforilação Oxidativa/efeitos dos fármacos
Consumo de Oxigênio/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Fosforilação/genética
Biossíntese de Proteínas/efeitos dos fármacos
Biossíntese de Proteínas/genética
Inibidores da Síntese de Proteínas/farmacologia
Ionóforos de Próton/farmacologia
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B); 0 (Histocompatibility Antigens); 0 (Protein Synthesis Inhibitors); 0 (Proton Ionophores); 0 (Reactive Oxygen Species); 370-86-5 (Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone); 642-15-9 (Antimycin A); 66974FR9Q1 (Chloramphenicol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14024


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[PMID]:28292919
[Au] Autor:Kulalert W; Sadeeshkumar H; Zhang YK; Schroeder FC; Kim DH
[Ad] Endereço:Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
[Ti] Título:Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2α Phosphorylation in .
[So] Source:Genetics;206(1):251-263, 2017 May.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell-nonautonomous effects of signaling in the nervous system of animals can influence diverse aspects of organismal physiology. We previously showed that phosphorylation of Ser49 of the α-subunit of eukaryotic translation initiation factor 2 (eIF2α) in two chemosensory neurons by PEK-1/PERK promotes entry of into dauer diapause. Here, we identified and characterized the molecular determinants that confer sensitivity to effects of neuronal eIF2α phosphorylation on development and physiology of Isolation and characterization of mutations in encoding the α-subunit of eIF2B support a conserved role, previously established by studies in yeast, for eIF2Bα in providing a binding site for phosphorylated eIF2α to inhibit the exchange factor eIF2B catalytic activity that is required for translation initiation. We also identified a mutation in , encoding the γ-subunit of eIF2, which confers insensitivity to the effects of phosphorylated eIF2α while also altering the requirement for eIF2Bγ. In addition, we show that constitutive expression of eIF2α carrying a phosphomimetic S49D mutation in the ASI pair of sensory neurons confers dramatic effects on growth, metabolism, and reproduction in adult transgenic animals, phenocopying systemic responses to starvation. Furthermore, we show that constitutive expression of eIF2α carrying a phosphomimetic S49D mutation in the ASI neurons enhances dauer entry through bypassing the requirement for nutritionally deficient conditions. Our data suggest that the state of eIF2α phosphorylation in the ASI sensory neuron pair may modulate internal nutrient sensing and signaling pathways, with corresponding organismal effects on development and metabolism.
[Mh] Termos MeSH primário: Caenorhabditis elegans/genética
Fator de Iniciação 2B em Eucariotos/genética
Fator de Iniciação 2 em Eucariotos/genética
Biossíntese de Proteínas
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Caenorhabditis elegans/crescimento & desenvolvimento
Fator de Iniciação 2 em Eucariotos/biossíntese
Fator de Iniciação 2B em Eucariotos/biossíntese
Mutação
Fosforilação
Células Receptoras Sensoriais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-2B)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.117.200568


  4 / 336 MEDLINE  
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[PMID]:28126977
[Au] Autor:Kashiwagi K; Ito T; Yokoyama S
[Ad] Endereço:RIKEN Center for Life Science Technologies.
[Ti] Título:[Three-dimensional Structure of eIF2B: A Clue to Understanding the Pathogenesis of CACH/VWM Disease].
[So] Source:Brain Nerve;69(1):45-50, 2017 Jan.
[Is] ISSN:1881-6096
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:CACH/VWM (childhood ataxia with central nervous system hypomyelination/vanishing white matter) disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B), but its etiology is poorly understood. Here, we attempt to provide an explanation for the pathogenic mechanism of this disease, based on the crystal structure of eIF2B.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/química
Leucoencefalopatias
Substância Branca/química
[Mh] Termos MeSH secundário: Fator de Iniciação 2B em Eucariotos/genética
Fator de Iniciação 2B em Eucariotos/metabolismo
Seres Humanos
Leucoencefalopatias/genética
Leucoencefalopatias/metabolismo
Modelos Moleculares
Mutação
Estrutura Quaternária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.11477/mf.1416200635


  5 / 336 MEDLINE  
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[PMID]:28093708
[Au] Autor:Zahoor I; Haq E; Asimi R
[Ad] Endereço:Department of Biotechnology, University of Kashmir, Srinagar, Jammu and Kashmir, India. inshazahoor11@gmail.com.
[Ti] Título:Multiple Sclerosis and EIF2B5: A Paradox or a Missing Link.
[So] Source:Adv Exp Med Biol;958:57-64, 2017.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multiple sclerosis (MS) is an encumbering inflammatory condition of the central nervous system (CNS) caused by axonal demyelination. There is sufficient evidence suggesting role of eukaryotic translation initiation factor 2B (EIF2B) gene family encoding the five subunits of eIF2B complex-α, ß, γ, δ and ε respectively, in causing vanishing white matter (VWM) disease of the brain. Incidentally researchers have proposed overlapping between MS and VWM in terms of clinical, biochemical and genetic aspects, which incited us to write this chapter to explore the association between EIF2B5 and MS. eIF2B plays an essential role in translation initiation and its regulation in eukaryotes. Among EIF2B gene family, EIF2B5 gene encodes the catalytic and a crucial epsilon subunit of the eIF2B protein as most of the alterations have been found in this gene. The recent findings on the association between EIF2B5 and MS susceptibility point towards unfathomable and contentious role of EIF2B5 in MS development. This chapter briefly reviews the insights gleaned from recent studies conducted in understanding the association between EIF2B5 and MS risk. The need of hour is to conduct large scale conclusive studies aimed at expounding the mechanisms behind this relationship.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/genética
Predisposição Genética para Doença
Esclerose Múltipla/genética
Mutação
[Mh] Termos MeSH secundário: Genótipo
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170118
[St] Status:MEDLINE
[do] DOI:10.1007/978-3-319-47861-6_5


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[PMID]:28041799
[Au] Autor:Lee JS; Lee S; Choi M; Lim BC; Choi J; Kim KJ; Cheon JE; Kim IO; Chae JH
[Ad] Endereço:Department of Pediatrics, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, South Korea.
[Ti] Título:eIF2B-related multisystem disorder in two sisters with atypical presentations.
[So] Source:Eur J Paediatr Neurol;21(2):404-409, 2017 Mar.
[Is] ISSN:1532-2130
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Vanishing white matter disease (VWM) is a chronic progressive leukoencephalopathy that is characterized by cerebellar ataxia and spasticity, together with cystic degeneration of the cerebral white matter as evidenced by brain magnetic resonance imaging (MRI). Here, we report two sisters with EIF2B2 variants, who presented with delayed development and failure to thrive before 1 year of age, developed cataracts, and showed diffuse leukoencephalopathy. CASE PRESENTATION: The index case had a history of hepatomegaly and intermittent vomiting after upper respiratory infection at 11 months of age. Her older brothers had died at an early age, one with similar symptoms and the other because of septic shock. Her older sister had similar presenting symptoms; she later suffered from both cataracts and primary amenorrhea, but showed neurological improvement. Her follow-up MRIs (at 21 years of age) revealed progressive diffuse brain atrophy with leukoencephalopathy, without cystic rarefaction. Whole-exome sequencing of the index case revealed the presence of the compound heterozygous variants, Val85Glu and Met226Lys in EIF2B2. The affected sister had the same compound heterozygous variants, and their unaffected parents were heterozygous carriers of each variant. CONCLUSIONS: This study expanded the clinical and genetic spectrum of VWM with EIF2B2 variants. It would be better to consider VWM as an eIF2B-related multisystem disorder, not just as a neurological disorder, on the basis that this is a family of housekeeping genes that affect multiple organs.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/genética
Leucoencefalopatias/genética
[Mh] Termos MeSH secundário: Adolescente
Pré-Escolar
Feminino
Heterozigoto
Seres Humanos
Leucoencefalopatias/patologia
Imagem por Ressonância Magnética
Masculino
Neuroimagem
Linhagem
Irmãos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170411
[Lr] Data última revisão:
170411
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170103
[St] Status:MEDLINE


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[PMID]:27627185
[Au] Autor:Kashiwagi K; Ito T; Yokoyama S
[Ad] Endereço:Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama, Japan.
[Ti] Título:Crystal structure of eIF2B and insights into eIF2-eIF2B interactions.
[So] Source:FEBS J;284(6):868-874, 2017 Mar.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Eukaryotic translation initiation factor 2B (eIF2B), a heterodecameric complex of two sets of the α, ß, γ, δ, and ε subunits, is the guanine nucleotide exchange factor (GEF) specific for eIF2, a heterotrimeric G protein consisting of the α, ß, and γ subunits. The eIF2 protein binds GTP on the γ subunits and delivers an initiator methionyl-tRNA (Met-tRNA ) to the ribosome. The GEF activity of eIF2B is inhibited by stress-induced phosphorylation of Ser51 in the α subunit of eIF2, which leads to lower amounts of active eIF2 and a limited quantity of Met-tRNA for the ribosome, resulting in global repression of translation. However, the structural mechanism of the GEF activity inhibition remained enigmatic, and therefore the three-dimensional structure of the entire eIF2B molecule had been awaited. Recently, we determined the crystal structure of Schizosaccharomyces pombe eIF2B. In this Structural Snapshot, we present the structural features of eIF2B and the mechanism underlying the GEF activity inhibition by the phosphorylation of eIF2α, elucidated from structure-based in vitro analyses.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/química
Fator de Iniciação 2 em Eucariotos/química
Conformação Proteica
Relação Estrutura-Atividade
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalografia por Raios X
Fator de Iniciação 2 em Eucariotos/metabolismo
Fator de Iniciação 2B em Eucariotos/metabolismo
Fatores de Troca do Nucleotídeo Guanina/química
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Fosforilação
Ligação Proteica
Aminoacil-RNA de Transferência/química
Aminoacil-RNA de Transferência/genética
Ribossomos/química
Ribossomos/genética
Schizosaccharomyces/química
Schizosaccharomyces/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2); 0 (Eukaryotic Initiation Factor-2B); 0 (Guanine Nucleotide Exchange Factors); 0 (RNA, Transfer, Amino Acyl); 0 (tRNA(m)(Met), methionine-)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170704
[Lr] Data última revisão:
170704
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160915
[St] Status:MEDLINE
[do] DOI:10.1111/febs.13896


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[PMID]:27812215
[Au] Autor:Sekine Y; Zyryanova A; Crespillo-Casado A; Amin-Wetzel N; Harding HP; Ron D
[Ad] Endereço:Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
[Ti] Título:Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells.
[So] Source:PLoS One;11(11):e0166278, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The eukaryotic translation initiation factor eIF2B promotes mRNA translation as a guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and the resultant phosphorylation of eIF2's alpha subunit (eIF2α) attenuates eIF2B GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in the ER. Mutations in all five subunits of human eIF2B cause an inherited leukoencephalopathy with vanishing white matter (VWM), but the role of the ISR in its pathogenesis remains unclear. Using CRISPR-Cas9 genome editing we introduced the most severe known VWM mutation, EIF2B4A391D, into CHO cells. Compared to isogenic wildtype cells, GEF activity of cells with the VWM mutation was impaired and the mutant cells experienced modest enhancement of the ISR. However, despite their enhanced ISR, imposed by the intrinsic defect in eIF2B, disrupting the inhibitory effect of phosphorylated eIF2α on GEF by a contravening EIF2S1/eIF2αS51A mutation that functions upstream of eIF2B, selectively enfeebled both EIF2B4A391D and the related severe VWM EIF2B4R483W cells. The basis for paradoxical dependence of cells with the VWM mutations on an intact eIF2α genotype remains unclear, as both translation rates and survival from stressors that normally activate the ISR were not reproducibly affected by the VWM mutations. Nonetheless, our findings support an additional layer of complexity in the development of VWM, beyond a hyperactive ISR.
[Mh] Termos MeSH primário: Estresse do Retículo Endoplasmático/genética
Fator de Iniciação 2B em Eucariotos/genética
Mutação
Substância Branca/citologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sequência de Bases
Células CHO
Linhagem Celular
Cricetinae
Cricetulus
Fator de Iniciação 2B em Eucariotos/química
Seres Humanos
Recombinação Genética
Resposta a Proteínas não Dobradas/genética
Substância Branca/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170628
[Lr] Data última revisão:
170628
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0166278


  9 / 336 MEDLINE  
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[PMID]:27458202
[Au] Autor:Jennings MD; Kershaw CJ; White C; Hoyle D; Richardson JP; Costello JL; Donaldson IJ; Zhou Y; Pavitt GD
[Ad] Endereço:Faculty of Biology Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK.
[Ti] Título:eIF2ß is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control.
[So] Source:Nucleic Acids Res;44(20):9698-9709, 2016 Nov 16.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. eIF2 GDP/GTP status is regulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2α phosphorylation in response to diverse signals is a major point of translational control. Here we characterize a growth suppressor mutation in eIF2ß that prevents eIF5 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation. By monitoring the binding of fluorescent nucleotides and initiator tRNA to purified eIF2 we show that the eIF2ß mutation does not affect intrinsic eIF2 affinities for these ligands, neither does it interfere with eIF2 binding to 43S pre-initiation complex components. Instead we show that the eIF2ß mutation prevents eIF5 GDI stabilizing nucleotide binding to eIF2, thereby altering the off-rate of GDP from eIF2•GDP/eIF5 complexes. This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 targets in response to amino acid starvation. These findings provide support for the importance of eIF5 GDI activity in vivo and demonstrate that eIF2ß acts in concert with eIF5 to prevent premature release of GDP from eIF2γ and thereby ensure tight control of protein synthesis initiation.
[Mh] Termos MeSH primário: Fator de Iniciação 2B em Eucariotos/metabolismo
Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo
Biossíntese de Proteínas
Proteínas Repressoras/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sequência Conservada
Fator de Iniciação 2B em Eucariotos/química
Fator de Iniciação 2B em Eucariotos/genética
Evolução Molecular
Inibidores de Dissociação do Nucleotídeo Guanina/química
Guanosina Difosfato/metabolismo
Guanosina Trifosfato/metabolismo
Modelos Moleculares
Mutação
Ligação Proteica
Conformação Proteica
RNA de Transferência/genética
RNA de Transferência/metabolismo
Proteínas Repressoras/química
Leveduras/efeitos dos fármacos
Leveduras/genética
Leveduras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Eukaryotic Initiation Factor-2B); 0 (Guanine Nucleotide Dissociation Inhibitors); 0 (Repressor Proteins); 146-91-8 (Guanosine Diphosphate); 86-01-1 (Guanosine Triphosphate); 9014-25-9 (RNA, Transfer)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160727
[St] Status:MEDLINE


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[PMID]:27273608
[Au] Autor:Betteridge ZE; Woodhead F; Lu H; Shaddick G; Bunn CC; Denton CP; Abraham DJ; du Bois RM; Lewis M; Wells AU; McHugh NJ
[Ad] Endereço:University of Bath, Bath, UK. z.e.betteridge@bath.ac.uk.
[Ti] Título:Brief Report: Anti-Eukaryotic Initiation Factor 2B Autoantibodies Are Associated With Interstitial Lung Disease in Patients With Systemic Sclerosis.
[So] Source:Arthritis Rheumatol;68(11):2778-2783, 2016 Nov.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To investigate novel systemic sclerosis (SSc) autoantibodies in autoantibody-negative patients and establish clinical associations. METHODS: Serum samples and clinical data for 548 patients with SSc were collected. Routine serologic techniques were used to test the serum samples for known SSc autoantibodies, and samples with negative results were further investigated by radiolabeled-protein immunoprecipitation assay. Sera that immunoprecipitated a novel 30-kd band were analyzed by indirect immunofluorescence and immunoprecipitation, using depleted cell extracts to establish a common reactivity. Mass spectrometry was performed to identify the novel autoantigen, and the results were confirmed using commercial antibodies. Sera from 426 patients with other forms of connective tissue disease, 103 with rheumatoid arthritis, 114 with idiopathic interstitial lung disease (ILD), and 150 healthy subjects were serotyped as controls. RESULTS: A novel autoantigen with a molecular weight of ∼30 kd was recognized by 7 sera from patients with SSc, 6 of whom had ILD, and by no controls. Six of the patients had diffuse cutaneous involvement, and 4 had overlap features with other autoimmune diseases. Immunodepletion experiments indicated that all samples targeted the same autoantigen, and mass spectrometry identified the novel autoantigen as eukaryotic initiation factor 2B (eIF2B). CONCLUSION: We report the identification of a novel autoantibody (anti-eIF2B) in a small number of patients with SSc (∼1%); this autoantibody is closely associated with diffuse cutaneous manifestations and the presence of ILD.
[Mh] Termos MeSH primário: Autoanticorpos/imunologia
Fator de Iniciação 2B em Eucariotos/imunologia
Doenças Pulmonares Intersticiais/imunologia
Escleroderma Sistêmico/imunologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Anticorpos Antinucleares/imunologia
Autoantígenos/imunologia
Western Blotting
Contraimunoeletroforese
DNA Topoisomerases Tipo I/imunologia
Feminino
Técnica Indireta de Fluorescência para Anticorpo
Seres Humanos
Imunoprecipitação
Doenças Pulmonares Intersticiais/etiologia
Masculino
Espectrometria de Massas
Meia-Idade
RNA Polimerase III/imunologia
Escleroderma Sistêmico/complicações
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Antinuclear); 0 (Autoantibodies); 0 (Autoantigens); 0 (Eukaryotic Initiation Factor-2B); 0 (anticentromere antibody); EC 2.7.7.6 (RNA Polymerase III); EC 5.99.1.2 (DNA Topoisomerases, Type I)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE
[do] DOI:10.1002/art.39755



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