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[PMID]:29281621
[Au] Autor:Tellier-Lebegue C; Dizet E; Ma E; Veaute X; Coïc E; Charbonnier JB; Maloisel L
[Ad] Endereço:I2BC, CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, Gif-sur-Yvette, France.
[Ti] Título:The translesion DNA polymerases Pol ζ and Rev1 are activated independently of PCNA ubiquitination upon UV radiation in mutants of DNA polymerase δ.
[So] Source:PLoS Genet;13(12):e1007119, 2017 12.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Replicative DNA polymerases cannot insert efficiently nucleotides at sites of base lesions. This function is taken over by specialized translesion DNA synthesis (TLS) polymerases to allow DNA replication completion in the presence of DNA damage. In eukaryotes, Rad6- and Rad18-mediated PCNA ubiquitination at lysine 164 promotes recruitment of TLS polymerases, allowing cells to efficiently cope with DNA damage. However, several studies showed that TLS polymerases can be recruited also in the absence of PCNA ubiquitination. We hypothesized that the stability of the interactions between DNA polymerase δ (Pol δ) subunits and/or between Pol δ and PCNA at the primer/template junction is a crucial factor to determine the requirement of PCNA ubiquitination. To test this hypothesis, we used a structural mutant of Pol δ in which the interaction between Pol3 and Pol31 is inhibited. We found that in yeast, rad18Δ-associated UV hypersensitivity is suppressed by pol3-ct, a mutant allele of the POL3 gene that encodes the catalytic subunit of replicative Pol δ. pol3-ct suppressor effect was specifically dependent on the Rev1 and Pol ζ TLS polymerases. This result strongly suggests that TLS polymerases could rely much less on PCNA ubiquitination when Pol δ interaction with PCNA is partially compromised by mutations. In agreement with this model, we found that the pol3-FI allele suppressed rad18Δ-associated UV sensitivity as observed for pol3-ct. This POL3 allele carries mutations within a putative PCNA Interacting Peptide (PIP) motif. We then provided molecular and genetic evidence that this motif could contribute to Pol δ-PCNA interaction indirectly, although it is not a bona fide PIP. Overall, our results suggest that the primary role of PCNA ubiquitination is to allow TLS polymerases to outcompete Pol δ for PCNA access upon DNA damage.
[Mh] Termos MeSH primário: DNA Polimerase III/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
DNA/genética
DNA/metabolismo
Dano ao DNA
DNA Polimerase III/genética
Reparo do DNA
Replicação do DNA
DNA Polimerase Dirigida por DNA/genética
DNA Polimerase Dirigida por DNA/metabolismo
Modelos Genéticos
Mutação
Nucleotidiltransferases/genética
Nucleotidiltransferases/metabolismo
Antígeno Nuclear de Célula em Proliferação/genética
Antígeno Nuclear de Célula em Proliferação/metabolismo
Ligação Proteica
Saccharomyces cerevisiae
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Ubiquitinação
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Proliferating Cell Nuclear Antigen); 0 (Saccharomyces cerevisiae Proteins); 9007-49-2 (DNA); EC 2.7.7.- (DNA Polymerase III); EC 2.7.7.- (DNA polymerase zeta); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.- (REV1 protein, S cerevisiae); EC 2.7.7.7 (DNA-Directed DNA Polymerase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007119


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[PMID]:29242153
[Au] Autor:Raj R; Mitra S; Gopal B
[Ad] Endereço:Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
[Ti] Título:Characterization of Staphylococcus epidermidis Polynucleotide phosphorylase and its interactions with ribonucleases RNase J1 and RNase J2.
[So] Source:Biochem Biophys Res Commun;495(2):2078-2084, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Polynucleotide phosphorylase catalyzes both 3'-5' exoribonuclease and polyadenylation reactions. The crystal structure of Staphylococcus epidermidis PNPase revealed a bound phosphate in the PH2 domain of each protomer coordinated by three adjacent serine residues. Mutational analysis suggests that phosphate coordination by these serine residues is essential to maintain the catalytic center in an active conformation. We note that PNPase forms a complex with RNase J1 and RNase J2 without substantially altering either exo-ribonuclease or polyadenylation activity of this enzyme. This decoupling of catalytic activity from protein-protein interactions suggests that association of these endo- or exo-ribonucleases with PNPase could be more relevant for cellular localization or concerted targeting of structured RNA for recycling.
[Mh] Termos MeSH primário: Simulação de Acoplamento Molecular
Nucleotidiltransferases/química
Nucleotidiltransferases/ultraestrutura
Ribonucleases/química
Ribonucleases/ultraestrutura
Staphylococcus epidermidis/enzimologia
[Mh] Termos MeSH secundário: Sítios de Ligação
Ativação Enzimática
Estabilidade Enzimática
Modelos Químicos
Complexos Multienzimáticos
Ligação Proteica
Conformação Proteica
Relação Estrutura-Atividade
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Multienzyme Complexes); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.- (polynucleotide pyrophosphorylase); EC 3.1.- (Ribonucleases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


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[PMID]:29258359
[Au] Autor:Sebastián M; Anoz-Carbonell E; Gracia B; Cossio P; Aínsa JA; Lans I; Medina M
[Ad] Endereço:a Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias , Universidad de Zaragoza , Zaragoza , Spain.
[Ti] Título:Discovery of antimicrobial compounds targeting bacterial type FAD synthetases.
[So] Source:J Enzyme Inhib Med Chem;33(1):241-254, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The increase of bacterial strains resistant to most of the available antibiotics shows a need to explore novel antibacterial targets to discover antimicrobial drugs. Bifunctional bacterial FAD synthetases (FADSs) synthesise the flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These cofactors act in vital processes as part of flavoproteins, making FADS an essential enzyme. Bacterial FADSs are potential antibacterial targets because of differences to mammalian enzymes, particularly at the FAD producing site. We have optimised an activity-based high throughput screening assay targeting Corynebacterium ammoniagenes FADS (CaFADS) that identifies inhibitors of its different activities. We selected the three best high-performing inhibitors of the FMN:adenylyltransferase activity (FMNAT) and studied their inhibition mechanisms and binding properties. The specificity of the CaFADS hits was evaluated by studying also their effect on the Streptococcus pneumoniae FADS activities, envisaging differences that can be used to discover species-specific antibacterial drugs. The antimicrobial effect of these compounds was also evaluated on C. ammoniagenes, S. pneumoniae, and Mycobacterium tuberculosis cultures, finding hits with favourable antimicrobial properties.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Corynebacterium/enzimologia
Descoberta de Drogas
Inibidores Enzimáticos/farmacologia
Nucleotidiltransferases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Corynebacterium/efeitos dos fármacos
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Testes de Sensibilidade Microbiana
Simulação de Acoplamento Molecular
Estrutura Molecular
Mycobacterium tuberculosis/efeitos dos fármacos
Nucleotidiltransferases/metabolismo
Streptococcus pneumoniae/efeitos dos fármacos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Enzyme Inhibitors); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.2 (FMN adenylyltransferase)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1411910


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[PMID]:28741459
[Au] Autor:Li Q; Huang YY; Conway LP; He M; Wei S; Huang K; Duan XC; Flitsch SL; Voglmeir J
[Ad] Endereço:Glycomics and Glycan Bioengineering Research Center (GGBRC), College of Food Science and Technology, Nanjing Agricultural University, Nanjing. China.
[Ti] Título:Discovery and Biochemical Characterization of a Thermostable Glucose-1-phosphate Nucleotidyltransferase from Thermodesulfatator indicus.
[So] Source:Protein Pept Lett;24(8):729-734, 2017.
[Is] ISSN:1875-5305
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The biosynthesis of NDP-glucoses is based on the nucleotide transfer from NTP donor substrates to glucose-1-phosphates catalyzed by glucose-1-phosphate nucleotidyltransferases. OBJECTIVES: The cloning and biochemical characterization of a glucose-1-phosphate nucleotidyltransferase (TiGPNT) from the deep sea bacterium Thermodesulfatator indicus. METHODS: The biochemical parameters of recombinant TiGPNT were determined using a plate reader-based coupled enzymatic assay, in which the reaction product UDP-glucose is oxidized in the presence of NAD+ forming UDP-Glucuronic acid and NADH. The substrate promiscuity of the enzyme was determined using thin-layer chromatography and MALDI-ToF mass spectrometry. RESULTS: TiGPNT was recombinantly expressed under the control of the T7 promoter in Escherichia coli and could be successfully enriched by heat treatment at 80°C for 30 min. The obtained enzyme worked best at pH 7.5 and the optimum reaction temperature was determined to be 50°C. Interestingly, TiGPNT could fully retain its activity even after extended incubation periods at temperatures of up to 80°C. The enzyme was strongly inhibited in the presence of Cu2+ and Fe2+ ions and EDTA. Among the tested glycosyl donor substrates, TiGPNT showed strict specificity towards glucose-1-phosphate. At the same time, TiGPNT was highly promiscuous towards all tested nucleotide donor substrates. CONCLUSION: TiGPNT shows comparable biochemical features in regards to pH optima, temperature optima and the substrate specificity to characterized glucose-1-phosphate nucleotidyltransferase from other species. The enzyme was capable of utilizing glucose-1-phosphate and all tested nucleoside triphosphate donors as substrates. The high activity of the enzyme and the simple purification protocol make TiGPNT an interesting new biocatalyst for the synthesis of glucose-diphospho nucleosides.
[Mh] Termos MeSH primário: Bactérias/química
Proteínas de Bactérias/metabolismo
Glucofosfatos/química
NAD/química
Uridina Difosfato Glucose/química
[Mh] Termos MeSH secundário: Organismos Aquáticos
Bactérias/enzimologia
Proteínas de Bactérias/genética
Clonagem Molecular
Estabilidade Enzimática
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Glucofosfatos/metabolismo
Temperatura Alta
Concentração de Íons de Hidrogênio
Cinética
NAD/metabolismo
Nucleotidiltransferases/genética
Nucleotidiltransferases/metabolismo
Plasmídeos/química
Plasmídeos/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Especificidade por Substrato
Uridina Difosfato Glucose/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Glucosephosphates); 0 (Recombinant Proteins); 0U46U6E8UK (NAD); CIX3U01VAU (glucose-1-phosphate); EC 2.7.7.- (Nucleotidyltransferases); V50K1D7P4Y (Uridine Diphosphate Glucose)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.2174/0929866524666170724110408


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[PMID]:29028835
[Au] Autor:Mullen NJ; Price DH
[Ad] Endereço:Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of America.
[Ti] Título:Hydrogen peroxide yields mechanistic insights into human mRNA capping enzyme function.
[So] Source:PLoS One;12(10):e0186423, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Capping of nascent RNA polymerase II (Pol II) transcripts is required for gene expression and the first two steps are catalyzed by separate 5' triphosphatase and guanylyltransferase activities of the human capping enzyme (HCE). The cap is added co-transcriptionally, but how the two activities are coordinated is unclear. Our previous in vitro work has suggested that an unidentified factor modulates the minimum length at which nascent transcripts can be capped. Using the same well-established in vitro system with hydrogen peroxide as a capping inhibitor, we show that this unidentified factor targets the guanylyltransferase activity of HCE. We also uncover the mechanism of HCE inhibition by hydrogen peroxide, and by using mass spectrometry demonstrate that the active site cysteine residue of the HCE triphosphatase domain becomes oxidized. Using recombinant proteins for the two separated HCE domains, we provide evidence that the triphosphatase normally acts on transcripts shorter than can be acted upon by the guanylyltransferase. Our further characterization of the capping reaction dependence on transcript length and its interaction with the unidentified modulator of capping raises the interesting possibility that the capping reaction could be regulated.
[Mh] Termos MeSH primário: Peróxido de Hidrogênio/farmacologia
Nucleosídeo-Trifosfatase/metabolismo
Nucleotidiltransferases/metabolismo
Capuzes de RNA/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Biocatálise
Inibidores Enzimáticos/farmacologia
Seres Humanos
Modelos Moleculares
Nucleosídeo-Trifosfatase/antagonistas & inibidores
Nucleosídeo-Trifosfatase/química
Nucleotidiltransferases/antagonistas & inibidores
Nucleotidiltransferases/química
Domínios Proteicos
Capuzes de RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (RNA Caps); BBX060AN9V (Hydrogen Peroxide); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.- (guanylyltransferase); EC 3.6.1.15 (Nucleoside-Triphosphatase)
[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:171014
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186423


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[PMID]:28968560
[Au] Autor:Gram AM; Sun C; Landman SL; Oosenbrug T; Koppejan HJ; Kwakkenbos MJ; Hoeben RC; Paludan SR; Ressing ME
[Ad] Endereço:Department Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: a.m.gram@lumc.nl.
[Ti] Título:Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure.
[So] Source:Mol Immunol;91:225-237, 2017 11.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Most cells are believed to be capable of producing type I interferons (IFN I) as part of an innate immune response against, for instance, viral infections. In macrophages, IFN I is potently induced upon cytoplasmic exposure to foreign nucleic acids. Infection of these cells with herpesviruses leads to triggering of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP (cGAMP) synthase (cGAS). Thereby, the stimulator of interferon genes (STING) and the downstream molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are sequentially activated culminating in IFN I secretion. Human gamma-herpesviruses, such as Epstein-Barr virus (EBV), exploit B cells as a reservoir for persistent infection. In this study, we investigated whether human B cells, similar to macrophages, engage the cytoplasmic DNA sensing pathway to induce an innate immune response. We found that the B cells fail to secrete IFN I upon cytoplasmic DNA exposure, although they express the DNA sensors cGAS and IFI16 and the signaling components TBK1 and IRF3. In primary human B lymphocytes and EBV-negative B cell lines, this deficiency is explained by a lack of detectable levels of the central adaptor protein STING. In contrast, EBV-transformed B cell lines did express STING, yet both these lines as well as STING-reconstituted EBV-negative B cells did not produce IFN I upon dsDNA or cGAMP stimulation. Our combined data show that the cytoplasmic DNA sensing pathway is dysfunctional in human B cells. This exemplifies that certain cell types cannot induce IFN I in response to cytoplasmic DNA exposure providing a potential niche for viral persistence.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
DNA/imunologia
Interferon Tipo I/imunologia
[Mh] Termos MeSH secundário: Linfócitos B/patologia
Linfócitos B/secreção
Linhagem Celular Transformada
DNA/metabolismo
Infecções por Vírus Epstein-Barr/imunologia
Infecções por Vírus Epstein-Barr/metabolismo
Infecções por Vírus Epstein-Barr/patologia
Feminino
Herpesvirus Humano 4/imunologia
Seres Humanos
Fator Regulador 3 de Interferon/imunologia
Fator Regulador 3 de Interferon/metabolismo
Interferon Tipo I/secreção
Masculino
Proteínas de Membrana/imunologia
Proteínas de Membrana/metabolismo
Proteínas Nucleares/imunologia
Proteínas Nucleares/metabolismo
Nucleotidiltransferases/imunologia
Nucleotidiltransferases/metabolismo
Fosfoproteínas/imunologia
Fosfoproteínas/metabolismo
Proteínas Serina-Treonina Quinases/imunologia
Proteínas Serina-Treonina Quinases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IRF3 protein, human); 0 (Interferon Regulatory Factor-3); 0 (Interferon Type I); 0 (MPYS protein, human); 0 (Membrane Proteins); 0 (Nuclear Proteins); 0 (Phosphoproteins); 148998-64-5 (IFI16 protein, human); 9007-49-2 (DNA); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171120
[Lr] Data última revisão:
171120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE


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[PMID]:28947539
[Au] Autor:Liu F; Niu Q; Fan X; Liu C; Zhang J; Wei Z; Hou W; Kanneganti TD; Robb ML; Kim JH; Michael NL; Sun J; Soong L; Hu H
[Ad] Endereço:Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
[Ti] Título:Priming and Activation of Inflammasome by Canarypox Virus Vector ALVAC via the cGAS/IFI16-STING-Type I IFN Pathway and AIM2 Sensor.
[So] Source:J Immunol;199(9):3293-3305, 2017 Nov 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Viral vectors derived from different virus families, including poxvirus (canarypox virus vector ALVAC) and adenovirus (human Ad5 vector), have been widely used in vaccine development for a range of human diseases including HIV/AIDS. Less is known about the mechanisms underlying the host innate response to these vectors. Increasing evidence from clinical vaccine trials testing different viral vectors has suggested the importance of understanding basic elements of host-viral vector interactions. In this study, we investigated the innate interactions of APCs with two commonly used HIV vaccine vectors, ALVAC and Ad5, and identified AIM2 as an innate sensor for ALVAC, triggering strong inflammasome activation in both human and mouse APCs. Microarray and comprehensive gene-knockout analyses (CRISPR/Cas9) identified that ALVAC stimulated the cGAS/IFI16-STING-type I IFN pathway to prime AIM2, which was functionally required for ALVAC-induced inflammasome activation. We also provided evidence that, in contrast to ALVAC, the Ad5 vector itself was unable to induce inflammasome activation, which was related to its inability to stimulate the STING-type I IFN pathway and to provide inflammasome-priming signals. In preconditioned APCs, the Ad5 vector could stimulate inflammasome activation through an AIM2-independent mechanism. Therefore, our study identifies the AIM2 inflammasome and cGAS/IFI16-STING-type I IFN pathway as a novel mechanism for host innate immunity to the ALVAC vaccine vector.
[Mh] Termos MeSH primário: Adenoviridae/imunologia
Células Apresentadoras de Antígenos/imunologia
Vírus da Varíola dos Canários/imunologia
Proteínas de Ligação a DNA/imunologia
Vetores Genéticos/imunologia
Imunidade Inata
Interferon Tipo I/imunologia
Proteínas de Membrana/imunologia
Proteínas Nucleares/imunologia
Nucleotidiltransferases/imunologia
Fosfoproteínas/imunologia
Transdução de Sinais/imunologia
[Mh] Termos MeSH secundário: Animais
Sistemas CRISPR-Cas
Proteínas de Ligação a DNA/genética
Feminino
Técnicas de Silenciamento de Genes
Seres Humanos
Interferon Tipo I/genética
Masculino
Proteínas de Membrana/genética
Camundongos
Camundongos Knockout
Proteínas Nucleares/genética
Nucleotidiltransferases/genética
Fosfoproteínas/genética
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AIM2 protein, human); 0 (Aim2 protein, mouse); 0 (DNA-Binding Proteins); 0 (Ifi16 protein, mouse); 0 (Interferon Type I); 0 (MPYS protein, human); 0 (MPYS protein, mouse); 0 (Membrane Proteins); 0 (Nuclear Proteins); 0 (Phosphoproteins); 148998-64-5 (IFI16 protein, human); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (MB21D1 protein, mouse); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700698


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[PMID]:28939760
[Au] Autor:Fang R; Wang C; Jiang Q; Lv M; Gao P; Yu X; Mu P; Zhang R; Bi S; Feng JM; Jiang Z
[Ad] Endereço:Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Beijing 100871, China.
[Ti] Título:NEMO-IKKß Are Essential for IRF3 and NF-κB Activation in the cGAS-STING Pathway.
[So] Source:J Immunol;199(9):3222-3233, 2017 Nov 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cytosolic dsDNA activates the cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway to produce cytokines, including type I IFNs. The roles of many critical proteins, including NEMO, IKKß, and TBK1, in this pathway are unclear because of the lack of an appropriate system to study. In this article, we report that lower FBS concentrations in culture medium conferred high sensitivities to dsDNA in otherwise unresponsive cells, whereas higher FBS levels abrogated this sensitivity. Based on this finding, we demonstrated genetically that NEMO was critically involved in the cGAS-STING pathway. Cytosolic DNA activated TRIM32 and TRIM56 to synthesize ubiquitin chains that bound NEMO and subsequently activated IKKß. Activated IKKß, but not IKKα, was required for TBK1 and NF-κB activation. In contrast, TBK1 was reciprocally required for NF-κB activation, probably by directly phosphorylating IKKß. Thus, our findings identified a unique innate immune activation cascade in which TBK1-IKKß formed a positive feedback loop to assure robust cytokine production during cGAS-STING activation.
[Mh] Termos MeSH primário: Quinase I-kappa B/imunologia
Fator Regulador 3 de Interferon/imunologia
Peptídeos e Proteínas de Sinalização Intracelular/imunologia
Proteínas de Membrana/imunologia
NF-kappa B/imunologia
Nucleotidiltransferases/imunologia
Transdução de Sinais/imunologia
[Mh] Termos MeSH secundário: Animais
Células HeLa
Seres Humanos
Quinase I-kappa B/genética
Fator Regulador 3 de Interferon/genética
Peptídeos e Proteínas de Sinalização Intracelular/genética
Células MCF-7
Proteínas de Membrana/genética
Camundongos
NF-kappa B/genética
Nucleotidiltransferases/genética
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IKBKG protein, human); 0 (IRF3 protein, human); 0 (Interferon Regulatory Factor-3); 0 (Intracellular Signaling Peptides and Proteins); 0 (Irf3 protein, mouse); 0 (MPYS protein, human); 0 (MPYS protein, mouse); 0 (Membrane Proteins); 0 (NEMO protein, mouse); 0 (NF-kappa B); EC 2.7.11.10 (I-kappa B Kinase); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (MB21D1 protein, mouse); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170924
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700699


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[PMID]:28934246
[Au] Autor:Hall J; Brault A; Vincent F; Weng S; Wang H; Dumlao D; Aulabaugh A; Aivazian D; Castro D; Chen M; Culp J; Dower K; Gardner J; Hawrylik S; Golenbock D; Hepworth D; Horn M; Jones L; Jones P; Latz E; Li J; Lin LL; Lin W; Lin D; Lovering F; Niljanskul N; Nistler R; Pierce B; Plotnikova O; Schmitt D; Shanker S; Smith J; Snyder W; Subashi T; Trujillo J; Tyminski E; Wang G; Wong J; Lefker B; Dakin L; Leach K
[Ad] Endereço:Medicine Design, Pfizer, Groton, Connecticut, United States of America.
[Ti] Título:Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay.
[So] Source:PLoS One;12(9):e0184843, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Nucleotidiltransferases/antagonistas & inibidores
Pirazóis/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/síntese química
Anti-Inflamatórios não Esteroides/farmacologia
Anticorpos/metabolismo
Descoberta de Drogas
Inibidores Enzimáticos/síntese química
Ensaio de Imunoadsorção Enzimática
Polarização de Fluorescência
Seres Humanos
Espectrometria de Massas
Modelos Moleculares
Estrutura Molecular
Nucleotídeos Cíclicos/imunologia
Nucleotidiltransferases/metabolismo
Ligação Proteica
Pirazóis/síntese química
Pirimidinas/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Antibodies); 0 (Enzyme Inhibitors); 0 (Nucleotides, Cyclic); 0 (PF-06928215); 0 (Pyrazoles); 0 (Pyrimidines); 0 (cyclic guanosine monophosphate-adenosine monophosphate); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184843


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[PMID]:28920955
[Au] Autor:Wu MZ; Cheng WC; Chen SF; Nieh S; O'Connor C; Liu CL; Tsai WW; Wu CJ; Martin L; Lin YS; Wu KJ; Lu LF; Izpisua Belmonte JC
[Ad] Endereço:Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
[Ti] Título:miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS.
[So] Source:Nat Cell Biol;19(10):1286-1296, 2017 Oct.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The mechanisms by which hypoxic tumours evade immunological pressure and anti-tumour immunity remain elusive. Here, we report that two hypoxia-responsive microRNAs, miR-25 and miR-93, are important for establishing an immunosuppressive tumour microenvironment by downregulating expression of the DNA sensor cGAS. Mechanistically, miR-25/93 targets NCOA3, an epigenetic factor that maintains basal levels of cGAS expression, leading to repression of cGAS during hypoxia. This allows hypoxic tumour cells to escape immunological responses induced by damage-associated molecular pattern molecules, specifically the release of mitochondrial DNA. Moreover, restoring cGAS expression results in an anti-tumour immune response. Clinically, decreased levels of cGAS are associated with poor prognosis for patients with breast cancer harbouring high levels of miR-25/93. Together, these data suggest that inactivation of the cGAS pathway plays a critical role in tumour progression, and reveal a direct link between hypoxia-responsive miRNAs and adaptive immune responses to the hypoxic tumour microenvironment, thus unveiling potential new therapeutic strategies.
[Mh] Termos MeSH primário: Neoplasias da Mama/enzimologia
MicroRNAs/metabolismo
Nucleotidiltransferases/metabolismo
Evasão Tumoral
[Mh] Termos MeSH secundário: Imunidade Adaptativa
Animais
Neoplasias da Mama/genética
Neoplasias da Mama/imunologia
Neoplasias da Mama/patologia
DNA Mitocondrial/genética
DNA Mitocondrial/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Progressão da Doença
Epigênese Genética
Feminino
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Células MCF-7
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
MicroRNAs/genética
Oxigenases de Função Mista/genética
Oxigenases de Função Mista/metabolismo
Coativador 3 de Receptor Nuclear/genética
Coativador 3 de Receptor Nuclear/metabolismo
Nucleotidiltransferases/genética
Proteínas Proto-Oncogênicas/genética
Proteínas Proto-Oncogênicas/metabolismo
Interferência de RNA
Receptor de Interferon alfa e beta/deficiência
Receptor de Interferon alfa e beta/genética
Transdução de Sinais
Fatores de Tempo
Transfecção
Hipóxia Tumoral
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Mitochondrial); 0 (DNA-Binding Proteins); 0 (MIRN25 microRNA, human); 0 (MIRN25 microRNA, mouse); 0 (MIRN93 microRNA, human); 0 (MicroRNAs); 0 (Mirn93 microRNA, mouse); 0 (Proto-Oncogene Proteins); 0 (TET1 protein, mouse); 156986-95-7 (Receptor, Interferon alpha-beta); EC 1.- (Mixed Function Oxygenases); EC 1.- (TET1 protein, human); EC 2.3.1.48 (NCOA3 protein, human); EC 2.3.1.48 (Ncoa3 protein, mouse); EC 2.3.1.48 (Nuclear Receptor Coactivator 3); EC 2.7.7.- (MB21D1 protein, human); EC 2.7.7.- (MB21D1 protein, mouse); EC 2.7.7.- (Nucleotidyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171028
[Lr] Data última revisão:
171028
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3615



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