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[PMID]:28471051
[Au] Autor:Döring C; Regen T; Gertig U; van Rossum D; Winkler A; Saiepour N; Brück W; Hanisch UK; Janova H
[Ad] Endereço:Institute of Neuropathology, University Medical Center Göttingen, Göttingen, 37075, Germany.
[Ti] Título:A presumed antagonistic LPS identifies distinct functional organization of TLR4 in mouse microglia.
[So] Source:Glia;65(7):1176-1185, 2017 Jul.
[Is] ISSN:1098-1136
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Microglia as principle innate immune cells of the central nervous system (CNS) are the first line of defense against invading pathogens. They are capable of sensing infections through diverse receptors, such as Toll-like receptor 4 (TLR4). This receptor is best known for its ability to recognize bacterial lipopolysaccharide (LPS), a causative agent of gram-negative sepsis and septic shock. A putative, naturally occurring antagonist of TLR4 derives from the photosynthetic bacterium Rhodobacter sphaeroides. However, the antagonistic potential of R. sphaeroides LPS (Rs-LPS) is no universal feature, since several studies suggested agonistic rather than antagonistic actions of this molecule depending on the investigated mammalian species. Here we show the agonistic versus antagonistic potential of Rs-LPS in primary mouse microglia. We demonstrate that Rs-LPS efficiently induces the release of cytokines and chemokines, which depends on TLR4, MyD88, and TRIF, but not CD14. Furthermore, Rs-LPS is able to regulate the phagocytic capacity of microglia as agonist, while it antagonizes Re-LPS-induced MHC I expression. Finally, to our knowledge, we are the first to provide in vivo evidence for an agonistic potential of Rs-LPS, as it efficiently triggers the recruitment of peripheral immune cells to the endotoxin-challenged CNS. Together, our results argue for a versatile and complex organization of the microglial TLR4 system, which specifically translates exogenous signals into cellular functions. Importantly, as demonstrated here for microglia, the antagonistic potential of Rs-LPS needs to be considered with caution, as reactions to Rs-LPS not only differ by cell type, but even by function within one cell type.
[Mh] Termos MeSH primário: Lipopolissacarídeos/farmacologia
Microglia/efeitos dos fármacos
Receptor 4 Toll-Like/antagonistas & inibidores
Receptor 4 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/genética
Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Animais
Animais Recém-Nascidos
Encéfalo/citologia
Células Cultivadas
Corpo Estriado/efeitos dos fármacos
Citocinas/metabolismo
Relação Dose-Resposta a Droga
Receptores de Lipopolissacarídeos/genética
Receptores de Lipopolissacarídeos/metabolismo
Macrófagos/efeitos dos fármacos
Macrófagos/fisiologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Bainha de Mielina/efeitos dos fármacos
Bainha de Mielina/patologia
Fator 88 de Diferenciação Mieloide/genética
Fator 88 de Diferenciação Mieloide/metabolismo
Fagocitose/efeitos dos fármacos
Fagocitose/fisiologia
Receptor 4 Toll-Like/genética
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Cytokines); 0 (Lipopolysaccharide Receptors); 0 (Lipopolysaccharides); 0 (Myeloid Differentiation Factor 88); 0 (TICAM-1 protein, mouse); 0 (Tlr4 protein, mouse); 0 (Toll-Like Receptor 4)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/glia.23151


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[PMID]:29362354
[Au] Autor:Garcia-Alai MM; Heidemann J; Skruzny M; Gieras A; Mertens HDT; Svergun DI; Kaksonen M; Uetrecht C; Meijers R
[Ad] Endereço:European Molecular Biology Laboratory (EMBL), Hamburg Outstation, Notkestrasse 85, 22607, Hamburg, Germany.
[Ti] Título:Epsin and Sla2 form assemblies through phospholipid interfaces.
[So] Source:Nat Commun;9(1):328, 2018 01 23.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In clathrin-mediated endocytosis, adapter proteins assemble together with clathrin through interactions with specific lipids on the plasma membrane. However, the precise mechanism of adapter protein assembly at the cell membrane is still unknown. Here, we show that the membrane-proximal domains ENTH of epsin and ANTH of Sla2 form complexes through phosphatidylinositol 4,5-bisphosphate (PIP2) lipid interfaces. Native mass spectrometry reveals how ENTH and ANTH domains form assemblies by sharing PIP2 molecules. Furthermore, crystal structures of epsin Ent2 ENTH domain from S. cerevisiae in complex with PIP2 and Sla2 ANTH domain from C. thermophilum illustrate how allosteric phospholipid binding occurs. A comparison with human ENTH and ANTH domains reveal only the human ENTH domain can form a stable hexameric core in presence of PIP2, which could explain functional differences between fungal and human epsins. We propose a general phospholipid-driven multifaceted assembly mechanism tolerating different adapter protein compositions to induce endocytosis.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/química
Proteínas Fúngicas/química
Fosfatidilinositol 4,5-Difosfato/química
Domínios Proteicos
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/genética
Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Sequência de Aminoácidos
Sítios de Ligação/genética
Membrana Celular/metabolismo
Chaetomium/genética
Chaetomium/metabolismo
Cristalografia por Raios X
Endocitose
Proteínas Fúngicas/genética
Proteínas Fúngicas/metabolismo
Seres Humanos
Modelos Moleculares
Fosfatidilinositol 4,5-Difosfato/metabolismo
Ligação Proteica
Multimerização Proteica
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/metabolismo
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Fungal Proteins); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (epsin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02443-x


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[PMID]:28743825
[Au] Autor:Navarro Negredo P; Edgar JR; Wrobel AG; Zaccai NR; Antrobus R; Owen DJ; Robinson MS
[Ad] Endereço:Cambridge Institute for Medical Research, University of Cambridge, Cambridge, England, UK.
[Ti] Título:Contribution of the clathrin adaptor AP-1 subunit µ1 to acidic cluster protein sorting.
[So] Source:J Cell Biol;216(9):2927-2943, 2017 Sep 04.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acidic clusters act as sorting signals for packaging cargo into clathrin-coated vesicles (CCVs), and also facilitate down-regulation of MHC-I by HIV-1 Nef. To find acidic cluster sorting machinery, we performed a gene-trap screen and identified the medium subunit (µ1) of the clathrin adaptor AP-1 as a top hit. In µ1 knockout cells, intracellular CCVs still form, but acidic cluster proteins are depleted, although several other CCV components were either unaffected or increased, indicating that cells can compensate for long-term loss of AP-1. In vitro experiments showed that the basic patch on µ1 that interacts with the Nef acidic cluster also contributes to the binding of endogenous acidic cluster proteins. Surprisingly, µ1 mutant proteins lacking the basic patch and/or the tyrosine-based motif binding pocket could rescue the µ1 knockout phenotype completely. In contrast, these mutants failed to rescue Nef-induced down-regulation of MHC class I, suggesting a possible mechanism for attacking the virus while sparing the host cell.
[Mh] Termos MeSH primário: Complexo 1 de Proteínas Adaptadoras/metabolismo
Subunidades mu do Complexo de Proteínas Adaptadoras/metabolismo
Vesículas Revestidas por Clatrina/metabolismo
HIV-1/metabolismo
Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
[Mh] Termos MeSH secundário: Complexo 1 de Proteínas Adaptadoras/química
Complexo 1 de Proteínas Adaptadoras/genética
Subunidades mu do Complexo de Proteínas Adaptadoras/química
Subunidades mu do Complexo de Proteínas Adaptadoras/genética
Sistemas CRISPR-Cas
Citometria de Fluxo
Técnicas de Silenciamento de Genes
Genótipo
Células HEK293
HIV-1/genética
Células HeLa
Antígenos de Histocompatibilidade Classe I/genética
Antígenos de Histocompatibilidade Classe I/metabolismo
Interações Hospedeiro-Patógeno
Seres Humanos
Modelos Moleculares
Mutação
Fenótipo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Transporte Proteico
Relação Estrutura-Atividade
Fatores de Tempo
Transfecção
Produtos do Gene nef do Vírus da Imunodeficiência Humana/química
Produtos do Gene nef do Vírus da Imunodeficiência Humana/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AP1M1 protein, human); 0 (Adaptor Protein Complex 1); 0 (Adaptor Protein Complex mu Subunits); 0 (Histocompatibility Antigens Class I); 0 (nef Gene Products, Human Immunodeficiency Virus); 0 (nef protein, Human immunodeficiency virus 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201602058


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[PMID]:28453927
[Au] Autor:Gentle IE; McHenry KT; Weber A; Metz A; Kretz O; Porter D; Häcker G
[Ad] Endereço:Faculty of Medicine, Institute for Medical Microbiology and Hygiene, Medical Center - University of Freiburg, University of Freiburg, Germany.
[Ti] Título:TIR-domain-containing adapter-inducing interferon-ß (TRIF) forms filamentous structures, whose pro-apoptotic signalling is terminated by autophagy.
[So] Source:FEBS J;284(13):1987-2003, 2017 07.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The formation of amyloid-like protein structures has recently emerged as a feature in signal transduction, particularly in innate immunity. These structures appear to depend on defined domains for their formation but likely also require dedicated ways to terminate signalling. We, here, define the innate immunity protein/Toll-like receptor adaptor TIR-domain-containing adapter-inducing interferon-ß (TRIF) as a novel platform of fibril formation and probe signal initiation through TRIF as well as its termination in Toll-like receptor 3 (TLR3)-stimulated melanoma cells. A main signalling pathway triggered by TLR3 caused apoptosis, which was controlled by inhibitor of apoptosis proteins and was dependent on RIPK1 and independent of TNF. Using correlative electron/fluorescence microscopy, we visualised fibrillar structures formed through both Toll/interleukin-1 receptor and RIP homotypic interacting motif regions of TRIF. We provide evidence that these fibrillary structures are active signalling platforms whose activity is terminated by autophagy. TRIF-signalling enhanced autophagy, and fibrillary structures were partly contained within autophagosomes. Inhibition of autophagy increased levels of pro-apoptotic TRIF complexes, leading to the accumulation of active caspase-8 and enhanced apoptosis while stimulation of autophagy reduced TRIF-dependent death. We conclude that pro-death signals through TRIF are regulated by autophagy and propose that pro-apoptotic signalling through TRIF/RIPK1/caspase-8 occurs in fibrillary platforms.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Apoptose/fisiologia
Autofagia/fisiologia
Transdução de Sinais
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/química
Proteínas Adaptadoras de Transporte Vesicular/genética
Animais
Apoptose/efeitos dos fármacos
Autofagia/efeitos dos fármacos
Western Blotting
Caspase 8/genética
Caspase 8/metabolismo
Linhagem Celular Tumoral
Células Cultivadas
Células HEK293
Células HeLa
Seres Humanos
Camundongos Knockout
Microscopia Eletrônica de Transmissão
Microscopia de Fluorescência
Oligopeptídeos/farmacologia
Poli I-C/farmacologia
Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
Receptor 3 Toll-Like/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (LBW242); 0 (Oligopeptides); 0 (TICAM1 protein, human); 0 (Toll-Like Receptor 3); EC 2.7.11.1 (RIPK1 protein, human); EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases); EC 3.4.22.- (Caspase 8); O84C90HH2L (Poly I-C)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14091


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[PMID]:28742265
[Au] Autor:Alsubhi S; Alhashem A; Faqeih E; Alfadhel M; Alfaifi A; Altuwaijri W; Alsahli S; Aldhalaan H; Alkuraya FS; Hundallah K; Mahmoud A; Alasmari A; Mutairi FA; Abduraouf H; AlRasheed L; Alshahwan S; Tabarki B
[Ad] Endereço:Division of Pediatric Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
[Ti] Título:Congenital disorders of glycosylation: The Saudi experience.
[So] Source:Am J Med Genet A;173(10):2614-2621, 2017 Oct.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We retrospectively reviewed Saudi patients who had a congenital disorder of glycosylation (CDG). Twenty-seven Saudi patients (14 males, 13 females) from 13 unrelated families were identified. Based on molecular studies, the 27 CDG patients were classified into different subtypes: ALG9-CDG (8 patients, 29.5%), ALG3-CDG (7 patients, 26%), COG6-CDG (7 patients, 26%), MGAT2-CDG (3 patients, 11%), SLC35A2-CDG (1 patient), and PMM2-CDG (1 patient). All the patients had homozygous gene mutations. The combined carrier frequency of CDG for the encountered founder mutations in the Saudi population is 11.5 per 10,000, which translates to a minimum disease burden of 14 patients per 1,000,000. Our study provides comprehensive epidemiologic information and prevalence figures for each of these CDG in a large cohort of congenital disorder of glycosylation patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Defeitos Congênitos da Glicosilação/genética
Mutação
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/genética
Adolescente
Criança
Pré-Escolar
Defeitos Congênitos da Glicosilação/epidemiologia
Feminino
Glicosilação
Homozigoto
Seres Humanos
Lactente
Masculino
Manosiltransferases/genética
Proteínas de Membrana/genética
Oxigenases de Função Mista/genética
Proteínas de Transporte de Monossacarídeos/genética
N-Acetilglucosaminiltransferases/genética
Fenótipo
Estudos Retrospectivos
Arábia Saudita/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Biomarkers, Tumor); 0 (COG6 protein, human); 0 (Membrane Proteins); 0 (Monosaccharide Transport Proteins); 0 (UDP-galactose translocator); EC 1.- (Mixed Function Oxygenases); EC 1.14.17.- (4-coumaroyl-D-glucose hydroxylase); EC 2.4.1.- (ALG3 protein, human); EC 2.4.1.- (ALG9 protein, human); EC 2.4.1.- (Mannosyltransferases); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.143 (alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.38358


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[PMID]:28459433
[Au] Autor:Ulas T; Pirr S; Fehlhaber B; Bickes MS; Loof TG; Vogl T; Mellinger L; Heinemann AS; Burgmann J; Schöning J; Schreek S; Pfeifer S; Reuner F; Völlger L; Stanulla M; von Köckritz-Blickwede M; Glander S; Barczyk-Kahlert K; von Kaisenberg CS; Friesenhagen J; Fischer-Riepe L; Zenker S; Schultze JL; Roth J; Viemann D
[Ad] Endereço:Genomics and Immunoregulation, LIMES-Institut, University of Bonn, Bonn, Germany.
[Ti] Título:S100-alarmin-induced innate immune programming protects newborn infants from sepsis.
[So] Source:Nat Immunol;18(6):622-632, 2017 Jun.
[Is] ISSN:1529-2916
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The high risk of neonatal death from sepsis is thought to result from impaired responses by innate immune cells; however, the clinical observation of hyperinflammatory courses of neonatal sepsis contradicts this concept. Using transcriptomic, epigenetic and immunological approaches, we demonstrated that high amounts of the perinatal alarmins S100A8 and S100A9 specifically altered MyD88-dependent proinflammatory gene programs. S100 programming prevented hyperinflammatory responses without impairing pathogen defense. TRIF-adaptor-dependent regulatory genes remained unaffected by perinatal S100 programming and responded strongly to lipopolysaccharide, but were barely expressed. Steady-state expression of TRIF-dependent genes increased only gradually during the first year of life in human neonates, shifting immune regulation toward the adult phenotype. Disruption of this critical sequence of transient alarmin programming and subsequent reprogramming of regulatory pathways increased the risk of hyperinflammation and sepsis. Collectively these data suggest that neonates are characterized by a selective, transient microbial unresponsiveness that prevents harmful hyperinflammation in the delicate neonate while allowing for sufficient immunological protection.
[Mh] Termos MeSH primário: Calgranulina A/imunologia
Calgranulina B/imunologia
Imunidade Inata/imunologia
Monócitos/imunologia
Sepse Neonatal/imunologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/genética
Proteínas Adaptadoras de Transporte Vesicular/imunologia
Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Animais
Animais Recém-Nascidos
Calgranulina A/efeitos dos fármacos
Calgranulina B/efeitos dos fármacos
Epigênese Genética
Sangue Fetal
Citometria de Fluxo
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Seres Humanos
Imunidade Inata/efeitos dos fármacos
Immunoblotting
Recém-Nascido
Inflamação
Lipopolissacarídeos/farmacologia
Camundongos
Camundongos Knockout
Monócitos/efeitos dos fármacos
Fator 88 de Diferenciação Mieloide/genética
Fator 88 de Diferenciação Mieloide/imunologia
Sepse Neonatal/genética
Reação em Cadeia da Polimerase em Tempo Real
Receptor 4 Toll-Like/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Calgranulin A); 0 (Calgranulin B); 0 (Lipopolysaccharides); 0 (Myeloid Differentiation Factor 88); 0 (TICAM-1 protein, mouse); 0 (TICAM1 protein, human); 0 (Toll-Like Receptor 4)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1038/ni.3745


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[PMID]:28747347
[Au] Autor:Ye W; Hu MM; Lei CQ; Zhou Q; Lin H; Sun MS; Shu HB
[Ad] Endereço:College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
[Ti] Título:TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Response by Blocking TRIF-TBK1 Interaction.
[So] Source:J Immunol;199(5):1856-1864, 2017 09 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:TLR-mediated signaling pathways play critical roles in host defense against microbials. However, dysregulation of innate immune and inflammatory responses triggered by TLRs would result in harmful damage to the host. Using a gene-knockout mouse model, we show that tripartite motif (TRIM) 8 negatively regulates TLR3- and TLR4-mediated innate immune and inflammatory responses. TRIM8 deficiency leads to increased polyinosinic-polycytidylic acid- and LPS-triggered induction of downstream anti-microbial genes including , , , and , evaluated serum cytokine levels, and increased susceptibility of mice to polyinosinic-polycytidylic acid- and LPS-induced inflammatory death as well as infection-induced loss of body weight and septic shock. TRIM8 interacted with Toll/IL-1 receptor domain-containing adapter-inducing IFN-ß and mediated its K6- and K33-linked polyubiquitination, leading to disruption of the Toll/IL-1 receptor domain-containing adapter-inducing IFN-ß-TANK-binding kinase-1 association. Our findings uncover an additional mechanism on the termination of TLR3/4-mediated inflammatory and innate immune responses.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Proteínas de Transporte/metabolismo
Inflamação/imunologia
Proteínas do Tecido Nervoso/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Infecções por Salmonella/imunologia
Salmonella typhimurium/imunologia
Choque Séptico/imunologia
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/genética
Citocinas/genética
Citocinas/metabolismo
Células HEK293
Seres Humanos
Imunidade Inata
Inflamação/microbiologia
Mediadores da Inflamação/metabolismo
Lipopolissacarídeos/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteínas do Tecido Nervoso/genética
Poli I-C/imunologia
Ligação Proteica
Transdução de Sinais
Receptor 3 Toll-Like/metabolismo
Receptor 4 Toll-Like/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Carrier Proteins); 0 (Cytokines); 0 (Inflammation Mediators); 0 (Lipopolysaccharides); 0 (Nerve Tissue Proteins); 0 (TICAM-1 protein, mouse); 0 (TLR3 protein, mouse); 0 (Tlr4 protein, mouse); 0 (Toll-Like Receptor 3); 0 (Toll-Like Receptor 4); 0 (Trim8 protein, mouse); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TBK1 protein, human); O84C90HH2L (Poly I-C)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180129
[Lr] Data última revisão:
180129
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601647


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[PMID]:28465426
[Au] Autor:Pryke KM; Abraham J; Sali TM; Gall BJ; Archer I; Liu A; Bambina S; Baird J; Gough M; Chakhtoura M; Haddad EK; Kirby IT; Nilsen A; Streblow DN; Hirsch AJ; Smith JL; DeFilippis VR
[Ad] Endereço:Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, Oregon, USA.
[Ti] Título:A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses.
[So] Source:MBio;8(3), 2017 May 02.
[Is] ISSN:2150-7511
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy's potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3- ]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/agonistas
Antivirais/farmacologia
Benzopiranos/farmacologia
Vírus Chikungunya/fisiologia
Vírus da Dengue/fisiologia
Tiadiazóis/farmacologia
Replicação Viral
Zika virus/fisiologia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Antivirais/química
Antivirais/isolamento & purificação
Benzopiranos/química
Benzopiranos/isolamento & purificação
Linhagem Celular
Febre de Chikungunya/tratamento farmacológico
Vírus Chikungunya/efeitos dos fármacos
Citocinas/biossíntese
Replicação do DNA/efeitos dos fármacos
Dengue/tratamento farmacológico
Vírus da Dengue/efeitos dos fármacos
Vírus da Dengue/metabolismo
Descoberta de Drogas
Edição de Genes
Interações Hospedeiro-Patógeno
Seres Humanos
Evasão da Resposta Imune
Imunidade Inata/efeitos dos fármacos
Fator Regulador 3 de Interferon/genética
Fator Regulador 3 de Interferon/metabolismo
Interferon Tipo I/efeitos dos fármacos
Interferon Tipo I/metabolismo
Interferon Tipo I/secreção
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/imunologia
Tiadiazóis/química
Tiadiazóis/isolamento & purificação
Zika virus/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Antiviral Agents); 0 (Benzopyrans); 0 (Cytokines); 0 (Interferon Regulatory Factor-3); 0 (Interferon Type I); 0 (TICAM1 protein, human); 0 (Thiadiazoles)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180126
[Lr] Data última revisão:
180126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:29179200
[Au] Autor:Rinné S; Kiper AK; Schmidt C; Ortiz-Bonnin B; Zwiener S; Seebohm G; Decher N
[Ad] Endereço:Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, Marburg, Germany.
[Ti] Título:Stress-Kinase Regulation of TASK-1 and TASK-3.
[So] Source:Cell Physiol Biochem;44(3):1024-1037, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: TASK channels belong to the two-pore-domain potassium (K2P) channel family. TASK-1 is discussed to contribute to chronic atrial fibrillation (AFib) and has been together with uncoupling protein 1 found as a marker protein of brown adipose tissue (BAT) fat. In addition, TASK-1 was linked in a genome-wide association study to an increased body mass index. A recent study showed that TASK-1 inhibition is causing obesity in mice by a BAT whitening and that these effects are linked to the mineralocorticoid receptor pathway, albeit the mechanism remained elusive. Therefore, we aimed to probe whether K2P channels are regulated by serum- and glucocorticoid-inducible kinases (SGKs) which are known to modify many cellular functions by modulating ion channels. METHODS: To this end we used functional co-expression studies and chemiluminescence-assays in Xenopus oocytes, together with fluorescence imaging and quantitative PCR experiments. RESULTS: SGKs and proteinkinase B (PKB) induced a strong, dose- and time-dependent current reduction of TASK-1 and TASK-3. SGK co-expression reduced the surface expression of TASK-1/3, leading to a predominant localization of the channels into late endosomes. The down regulation of TASK-3 channels was abrogated by the dynamin inhibitor dynasore, confirming a role of SGKs in TASK-1/3 channel endocytosis. CONCLUSION: Stress-mediated changes in SGK expression pattern or activation is likely to alter TASK-1/3 expression at the surface membrane. The observed TASK-1 regulation might contribute to the pathogenesis of chronic AFib and provide a mechanistic link between increased mineralocorticoid levels and TASK-1 reduction, both linked to BAT whitening.
[Mh] Termos MeSH primário: Proteínas do Tecido Nervoso/metabolismo
Canais de Potássio de Domínios Poros em Tandem/metabolismo
[Mh] Termos MeSH secundário: Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo
Animais
Células COS
Cercopithecus aethiops
Clatrina/metabolismo
Endocitose
Endossomos/metabolismo
Células HeLa
Seres Humanos
Hidrazonas/farmacologia
Proteínas Imediatamente Precoces/genética
Proteínas Imediatamente Precoces/metabolismo
Medições Luminescentes
Microscopia de Fluorescência
Proteínas do Tecido Nervoso/genética
Oócitos/química
Oócitos/fisiologia
Técnicas de Patch-Clamp
Plasmídeos/genética
Plasmídeos/metabolismo
Canais de Potássio de Domínios Poros em Tandem/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Imagem com Lapso de Tempo
Xenopus laevis/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Clathrin); 0 (Hydrazones); 0 (Immediate-Early Proteins); 0 (KCNK9 protein, human); 0 (N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide); 0 (Nerve Tissue Proteins); 0 (Potassium Channels, Tandem Pore Domain); 0 (potassium channel subfamily K member 3); EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases); EC 2.7.11.1 (PDPK1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.1 (serum-glucocorticoid regulated kinase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485402


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[PMID]:28456331
[Au] Autor:Zdanowicz R; Kreutzberger A; Liang B; Kiessling V; Tamm LK; Cafiso DS
[Ad] Endereço:Department of Chemistry, University of Virginia, Charlottesville, Virginia; Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, Virginia.
[Ti] Título:Complexin Binding to Membranes and Acceptor t-SNAREs Explains Its Clamping Effect on Fusion.
[So] Source:Biophys J;113(6):1235-1250, 2017 Sep 19.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complexin-1 is a SNARE effector protein that decreases spontaneous neurotransmitter release and enhances evoked release. Complexin binds to the fully assembled four-helical neuronal SNARE core complex as revealed in competing molecular models derived from x-ray crystallography. Presently, it is unclear how complexin binding to the postfusion complex accounts for its effects upon spontaneous and evoked release in vivo. Using a combination of spectroscopic and imaging methods, we characterize in molecular detail how complexin binds to the 1:1 plasma membrane t-SNARE complex of syntaxin-1a and SNAP-25 while simultaneously binding the lipid bilayer at both its N- and C-terminal ends. These interactions are cooperative, and binding to the prefusion acceptor t-SNARE complex is stronger than to the postfusion core complex. This complexin interaction reduces the affinity of synaptobrevin-2 for the 1:1 complex, thereby retarding SNARE assembly and vesicle docking in vitro. The results provide the basis for molecular models that account for the observed clamping effect of complexin beginning with the acceptor t-SNARE complex and the subsequent activation of the clamped complex by Ca and synaptotagmin.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Bicamadas Lipídicas/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Proteína 25 Associada a Sinaptossoma/metabolismo
Sintaxina 1/metabolismo
Proteína 2 Associada à Membrana da Vesícula/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/química
Proteínas Adaptadoras de Transporte Vesicular/genética
Animais
Escherichia coli
Bicamadas Lipídicas/química
Lipossomos/química
Lipossomos/metabolismo
Mutação
Proteínas do Tecido Nervoso/química
Proteínas do Tecido Nervoso/genética
Fosfatidilcolinas/química
Fosfatidilserinas/química
Ligação Proteica
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Propriedades de Superfície
Proteína 25 Associada a Sinaptossoma/química
Sintaxina 1/química
Proteína 2 Associada à Membrana da Vesícula/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Lipid Bilayers); 0 (Liposomes); 0 (Nerve Tissue Proteins); 0 (Phosphatidylcholines); 0 (Phosphatidylserines); 0 (Recombinant Proteins); 0 (Snap25 protein, rat); 0 (Synaptosomal-Associated Protein 25); 0 (Syntaxin 1); 0 (Vamp2 protein, rat); 0 (Vesicle-Associated Membrane Protein 2); 0 (complexin I); 40290-44-6 (1-palmitoyl-2-oleoylglycero-3-phosphoserine); TE895536Y5 (1-palmitoyl-2-oleoylphosphatidylcholine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171212
[Lr] Data última revisão:
171212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE



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