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Pesquisa : D12.776.543.990.150.875 [Categoria DeCS]
Referências encontradas : 365 [refinar]
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[PMID]:28960203
[Au] Autor:Rabouille C
[Ad] Endereço:Hubrecht Institute/KNAW and UMC Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands; and the Department of Cell Biology, UMC Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
[Ti] Título:Retriever fetches integrins from endosomes.
[So] Source:Nat Cell Biol;19(10):1144-1146, 2017 Sep 29.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recycling from endosomes to the plasma membrane is an important step in cell homeostasis. The retromer/SNX27/WASH complex recycles numerous receptors, but key ones are still unaccounted for. Now a related conserved heterotrimer, called retriever, has been identified that, together with SNX17, the CCC complex and WASH, mediates the recycling of α ß integrins.
[Mh] Termos MeSH primário: Integrinas
Nexinas de Classificação
[Mh] Termos MeSH secundário: Membrana Celular
Endossomos
Seres Humanos
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Integrins); 0 (Sorting Nexins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3612


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[PMID]:28892079
[Au] Autor:McNally KE; Faulkner R; Steinberg F; Gallon M; Ghai R; Pim D; Langton P; Pearson N; Danson CM; Nägele H; Morris LL; Singla A; Overlee BL; Heesom KJ; Sessions R; Banks L; Collins BM; Berger I; Billadeau DD; Burstein E; Cullen PJ
[Ad] Endereço:School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol BS8 1TD, UK.
[Ti] Título:Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling.
[So] Source:Nat Cell Biol;19(10):1214-1225, 2017 Oct.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Following endocytosis into the endosomal network, integral membrane proteins undergo sorting for lysosomal degradation or are retrieved and recycled back to the cell surface. Here we describe the discovery of an ancient and conserved multiprotein complex that orchestrates cargo retrieval and recycling and, importantly, is biochemically and functionally distinct from the established retromer pathway. We have called this complex 'retriever'; it is a heterotrimer composed of DSCR3, C16orf62 and VPS29, and bears striking similarity to retromer. We establish that retriever associates with the cargo adaptor sorting nexin 17 (SNX17) and couples to CCC (CCDC93, CCDC22, COMMD) and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of α ß integrin. Through quantitative proteomic analysis, we identify over 120 cell surface proteins, including numerous integrins, signalling receptors and solute transporters, that require SNX17-retriever to maintain their surface levels. Our identification of retriever establishes a major endosomal retrieval and recycling pathway.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Endossomos/metabolismo
Proteínas de Neoplasias/metabolismo
Proteínas/metabolismo
Proteínas de Transporte Vesicular/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Proteínas de Drosophila/genética
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/genética
Drosophila melanogaster/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Cinética
Modelos Moleculares
Complexos Multiproteicos
Proteínas de Neoplasias/química
Proteínas de Neoplasias/genética
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Estabilidade Proteica
Transporte Proteico
Proteínas/química
Proteínas/genética
Proteólise
Proteômica/métodos
Interferência de RNA
Nexinas de Classificação/genética
Nexinas de Classificação/metabolismo
Relação Estrutura-Atividade
Transfecção
Proteínas de Transporte Vesicular/química
Proteínas de Transporte Vesicular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C16orf62 protein, human); 0 (CCDC22 protein, human); 0 (DSCR3 protein, human); 0 (Drosophila Proteins); 0 (Multiprotein Complexes); 0 (Neoplasm Proteins); 0 (Proteins); 0 (SNX17 protein, human); 0 (Sorting Nexins); 0 (VPS29 protein, human); 0 (Vesicular Transport Proteins)
[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:170912
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3610


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[PMID]:28771744
[Au] Autor:Jitsukawa S; Kamekura R; Kawata K; Ito F; Sato A; Matsumiya H; Nagaya T; Yamashita K; Kubo T; Kikuchi T; Sato N; Hasegawa T; Kiyonari H; Mukumoto Y; Takano KI; Himi T; Ichimiya S
[Ad] Endereço:Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
[Ti] Título:Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression.
[So] Source:J Pathol;243(3):342-353, 2017 Nov.
[Is] ISSN:1096-9896
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well-differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5-deficient (Snx5 ) mice. In comparison to wild-type (Snx5 ) mice, Snx5 mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular-shaped vacuoles. Snx5 thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid-stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5 thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5 thyrocytes were also confirmed by results showing that Snx5 mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti-thyroidal agent revealed that Snx5 mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Nexinas de Classificação/genética
Neoplasias da Glândula Tireoide/patologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Progressão da Doença
Camundongos Transgênicos
Receptores de Fatores de Crescimento/metabolismo
Transdução de Sinais/fisiologia
Neoplasias da Glândula Tireoide/diagnóstico
Neoplasias da Glândula Tireoide/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Growth Factor); 0 (Snx5 protein, mouse); 0 (Sorting Nexins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170804
[St] Status:MEDLINE
[do] DOI:10.1002/path.4951


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[PMID]:28620080
[Au] Autor:Feng S; Streets AJ; Nesin V; Tran U; Nie H; Onopiuk M; Wessely O; Tsiokas L; Ong ACM
[Ad] Endereço:Kidney Genetics Group, Academic Nephrology Unit and the Bateson Centre, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom.
[Ti] Título:The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex.
[So] Source:J Am Soc Nephrol;28(10):2973-2984, 2017 Oct.
[Is] ISSN:1533-3450
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in (85%) or (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor-ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors. Using yeast two-hybrid, biochemical, and cellular assays, we determined that PC2 binds two isoforms of the retromer-associated protein sorting nexin 3 (SNX3), including a novel isoform that binds PC2 in a direct manner. Knockdown of SNX3 or the core retromer protein VPS35 increased the surface expression of endogenous PC1 and PC2 and and increased Wnt-activated PC2-dependent whole-cell currents. These findings indicate that an SNX3-retromer complex regulates the surface expression and function of PC1 and PC2. Molecular targeting of proteins involved in the endosomal sorting of PC1 and PC2 could lead to new therapeutic approaches in ADPKD.
[Mh] Termos MeSH primário: Endocitose
Nexinas de Classificação/metabolismo
Canais de Cátion TRPP/metabolismo
[Mh] Termos MeSH secundário: Animais
Células HEK293
Células HeLa
Seres Humanos
Túbulos Renais/metabolismo
Proteínas de Transporte Vesicular/metabolismo
Xenopus
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SNX3 protein, human); 0 (Sorting Nexins); 0 (TRPP Cation Channels); 0 (VPS35 protein, human); 0 (Vesicular Transport Proteins); 0 (polycystic kidney disease 1 protein); 0 (polycystic kidney disease 2 protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1681/ASN.2016121349


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[PMID]:28542875
[Au] Autor:Su K; Xu T; Yu Z; Zhu J; Zhang Y; Wu M; Xiong Y; Liu J; Xu J
[Ad] Endereço:School of Life Sciences, University of Science and Technology of China, Hefei, China.
[Ti] Título:Structure of the PX domain of SNX25 reveals a novel phospholipid recognition model by dimerization in the PX domain.
[So] Source:FEBS Lett;591(13):2011-2018, 2017 Jul.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:SNX25, a regulator of GPCR signaling-phox-homology (PX) domain containing sorting nexin (SNX) member, has been proposed to be involved in the lysosomal degradation of the transforming growth factor ß receptor and the development of temporal lobe epilepsy. Targeting to the endosomal membranes by the specific binding of phosphorylated phosphatidylinositols (PIPs) through the PX domain is critical for the function of SNXs. However, the mechanism for SNX25-PX targeting to the endosomes remains unclear. Here, we demonstrate that the PX domain of zebrafish SNX25 (zSNX25-PX) is capable of binding to PI3P only in its dimeric form. We also present the crystal structure of zSNX25-PX. Combined with biochemical experiments, we further identify a potential PI3P-binding region and propose a novel PI-binding model based on dimerization in the PX domain of SNXs.
[Mh] Termos MeSH primário: Fosfatidilinositóis/metabolismo
Multimerização Proteica
Nexinas de Classificação/genética
Nexinas de Classificação/metabolismo
Proteínas de Peixe-Zebra/química
Proteínas de Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Simulação de Acoplamento Molecular
Ligação Proteica
Domínios Proteicos
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Phosphatidylinositols); 0 (Snx25 protein, zebrafish); 0 (Sorting Nexins); 0 (Zebrafish Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12688


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[PMID]:28475030
[Au] Autor:Bergant M; Peternel S; Pim D; Broniarczyk J; Banks L
[Ad] Endereço:2​Centre for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, Slovenia 1​Laboratory for Environmental and Life Sciences, University of Nova Gorica, Nova Gorica, Slovenia.
[Ti] Título:Characterizing the spatio-temporal role of sorting nexin 17 in human papillomavirus trafficking.
[So] Source:J Gen Virol;98(4):715-725, 2017 Apr.
[Is] ISSN:1465-2099
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The human papillomavirus (HPV) L2 capsid protein plays an essential role during the early stages of viral infection. Previous studies have shown that the interaction between HPV L2 and endosomal sorting nexin 17 (SNX17) is conserved across multiple PV types where it plays an essential role in infectious entry, suggesting an evolutionarily conserved pathway of PV trafficking. Here we show that the peak time of interaction between HPV-16 L2 and SNX17 is rather early, at 2 h post-infection. Interestingly, the L2-SNX17 interaction appears to be important for facilitating capsid disassembly and L1 dissociation, suggesting that L2 recruitment of SNX17 occurs prior to capsid disassembly. Furthermore, we also found evidence of L2-SNX17 association at the later stages of infectious entry, suggesting that the SNX17-mediated sorting machinery is either involved at different stages of HPV trafficking or that L2-SNX17 interaction is a long-lasting event in HPV trafficking.
[Mh] Termos MeSH primário: Proteínas do Capsídeo/metabolismo
Proteínas Oncogênicas Virais/metabolismo
Papillomaviridae/metabolismo
Infecções por Papillomavirus/metabolismo
Nexinas de Classificação/metabolismo
[Mh] Termos MeSH secundário: Capsídeo/metabolismo
Proteínas do Capsídeo/genética
Endossomos/genética
Endossomos/metabolismo
Endossomos/virologia
Seres Humanos
Proteínas Oncogênicas Virais/genética
Papillomaviridae/genética
Infecções por Papillomavirus/genética
Infecções por Papillomavirus/virologia
Ligação Proteica
Nexinas de Classificação/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Capsid Proteins); 0 (L2 protein, Human papillomavirus type 16); 0 (Oncogene Proteins, Viral); 0 (SNX17 protein, human); 0 (Sorting Nexins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170607
[Lr] Data última revisão:
170607
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170506
[St] Status:MEDLINE
[do] DOI:10.1099/jgv.0.000734


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[PMID]:28404745
[Au] Autor:Dalton LE; Bean BDM; Davey M; Conibear E
[Ad] Endereço:Centre for Molecular Medicine and Therapeutics, BC Children's Hospital, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
[Ti] Título:Quantitative high-content imaging identifies novel regulators of Neo1 trafficking at endosomes.
[So] Source:Mol Biol Cell;28(11):1539-1550, 2017 Jun 01.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:P4-ATPases are a family of putative phospholipid flippases that regulate lipid membrane asymmetry, which is important for vesicle formation. Two yeast flippases, Drs2 and Neo1, have nonredundant functions in the recycling of the synaptobrevin-like v-SNARE Snc1 from early endosomes. Drs2 activity is needed to form vesicles and regulate its own trafficking, suggesting that flippase activity and localization are linked. However, the role of Neo1 in endosomal recycling is not well characterized. To identify novel regulators of Neo1 trafficking and activity at endosomes, we first identified mutants with impaired recycling of a Snc1-based reporter and subsequently used high-content microscopy to classify these mutants based on the localization of Neo1 or its binding partners, Mon2 and Dop1. This analysis identified a role for Arl1 in stabilizing the Mon2/Dop1 complex and uncovered a new function for Vps13 in early endosome recycling and Neo1 localization. We further showed that the cargo-selective sorting nexin Snx3 is required for Neo1 trafficking and identified an Snx3 sorting motif in the Neo1 N-terminus. Of importance, the Snx3-dependent sorting of Neo1 was required for the correct sorting of another Snx3 cargo protein, suggesting that the incorporation of Neo1 into recycling tubules may influence their formation.
[Mh] Termos MeSH primário: Adenosina Trifosfatases/metabolismo
Proteínas de Transporte/metabolismo
Endossomos/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Proteínas de Transferência de Fosfolipídeos/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Adenosina Trifosfatases/genética
Proteínas de Membrana Transportadoras/genética
Proteínas de Transferência de Fosfolipídeos/genética
Transporte Proteico/fisiologia
Proteínas SNARE/metabolismo
Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/genética
Nexinas de Classificação/metabolismo
Vesículas Transportadoras/metabolismo
Proteínas de Transporte Vesicular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Membrane Transport Proteins); 0 (Phospholipid Transfer Proteins); 0 (SNARE Proteins); 0 (SNX3 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (Sorting Nexins); 0 (Vesicular Transport Proteins); EC 3.6.1.- (Adenosine Triphosphatases); EC 3.6.3.1 (NEO1 protein, S cerevisiae)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1091/mbc.E16-11-0772


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[PMID]:28381192
[Au] Autor:Cervantes-Anaya N; Ponciano-Gómez A; López-Álvarez GS; Gonzalez-Reyes C; Hernández-Garcia S; Cabañas-Cortes MA; Garrido-Guerrero JE; Villa-Treviño S
[Ad] Endereço:1 Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados (CINVESTAV-IPN), Ciudad de México, México.
[Ti] Título:Downregulation of sorting nexin 10 is associated with overexpression of miR-30d during liver cancer progression in rats.
[So] Source:Tumour Biol;39(4):1010428317695932, 2017 Apr.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As of 2012, liver cancer was the second leading cause of death worldwide, and hepatocellular carcinoma is the most common primary cancer of the liver. The identification of molecules that might be molecular markers or therapeutic targets is urgently needed to improve clinical management. Based on a microarray analysis performed in our laboratory, we selected six genes-namely, ANXA2, DYNLT1, PFKP, PLA2G7, KRT19, and SNX10-as candidates for validation as tumor markers of liver cancer in a rat model. Their patterns of overexpression in preneoplastic lesions and established tumors at 10 different time points between 24 h and 18 months were analyzed to identify putative tumor markers for further studies. We validated the microarray results by quantitative reverse transcription polymerase chain reaction, which revealed high transcriptional expression for five of the genes, consistent with their high protein expression during cancer progression reported in the literature. However, studies of the association of sorting nexin 10 with different types of cancer are limited, prompting further study. The characterization of sorting nexin 10 in preneoplastic lesions and established tumors revealed messenger RNA overexpression and a simultaneous decrease in sorting nexin 10 protein expression. A group of microRNAs related to sorting nexin 10 messenger RNA were selected based on a data analysis conducted using miRDB and microrna.org . An analysis of the expression of these microRNAs revealed an increase in the transcription of microRNA-30d whenever the sorting nexin 10 protein was downregulated. These results suggest that sorting nexin 10 is a potential liver cancer marker exhibiting characteristics of a putative suppressor protein that is likely regulated by microRNA-30d.
[Mh] Termos MeSH primário: Neoplasias Hepáticas Experimentais/metabolismo
MicroRNAs/genética
Nexinas de Classificação/genética
[Mh] Termos MeSH secundário: Animais
Proteína 5 Relacionada à Autofagia/genética
Biomarcadores Tumorais/genética
Progressão da Doença
Regulação Neoplásica da Expressão Gênica
Neoplasias Hepáticas Experimentais/patologia
Masculino
MicroRNAs/análise
Ratos
Ratos Endogâmicos F344
Nexinas de Classificação/análise
Nexinas de Classificação/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Atg5 protein, rat); 0 (Autophagy-Related Protein 5); 0 (Biomarkers, Tumor); 0 (MIRN30 microRNA, rat); 0 (MicroRNAs); 0 (Sorting Nexins)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170418
[Lr] Data última revisão:
170418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170407
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317695932


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[PMID]:28335009
[Au] Autor:Fullard JF; Giambartolomei C; Hauberg ME; Xu K; Voloudakis G; Shao Z; Bare C; Dudley JT; Mattheisen M; Robakis NK; Haroutunian V; Roussos P
[Ad] Endereço:Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
[Ti] Título:Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci.
[So] Source:Hum Mol Genet;26(10):1942-1951, 2017 May 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell type markers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs are more evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism (SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.
[Mh] Termos MeSH primário: Cromatina/patologia
Regiões Promotoras Genéticas/genética
Esquizofrenia/fisiopatologia
[Mh] Termos MeSH secundário: Encéfalo/metabolismo
Mapeamento Encefálico/métodos
Cromatina/metabolismo
Imunoprecipitação da Cromatina/métodos
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/fisiologia
Elementos Facilitadores Genéticos/genética
Expressão Gênica/genética
Estudo de Associação Genômica Ampla
Seres Humanos
Polimorfismo de Nucleotídeo Único/genética
Regiões Promotoras Genéticas/fisiologia
Esquizofrenia/genética
Nexinas de Classificação/genética
Nexinas de Classificação/metabolismo
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (DNA-Binding Proteins); 0 (Sorting Nexins); 0 (Transcription Factors)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx103


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[PMID]:28109317
[Au] Autor:Kim NY; Cho MH; Won SH; Kang HJ; Yoon SY; Kim DH
[Ad] Endereço:Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
[Ti] Título:Sorting nexin-4 regulates ß-amyloid production by modulating ß-site-activating cleavage enzyme-1.
[So] Source:Alzheimers Res Ther;9(1):4, 2017 Jan 21.
[Is] ISSN:1758-9193
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Amyloid precursor protein (APP) is cleaved by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) to produce ß-amyloid (Aß), a critical pathogenic peptide in Alzheimer's disease (AD). Aß generation can be affected by the intracellular trafficking of APP or its related secretases, which is thus important to understanding its pathological alterations. Although sorting nexin (SNX) family proteins regulate this trafficking, the relevance and role of sorting nexin-4 (SNX4) regarding AD has not been studied yet. METHODS: In this study, human brain tissue and APP/PS1 mouse brain tissue were used to check the disease relevance of SNX4. To investigate the role of SNX4 in AD pathogenesis, several experiments were done, such as coimmunoprecipitation, Western blotting, immunohistochemistry, and gradient fractionation. RESULTS: We found that SNX4 protein levels changed in the brains of patients with AD and of AD model mice. Overexpression of SNX4 significantly increased the levels of BACE1 and Aß. Downregulation of SNX4 had the opposite effect. SNX4 interacts with BACE1 and prevents BACE1 trafficking to the lysosomal degradation system, resulting in an increased half-life of BACE1 and increased production of Aß. CONCLUSIONS: We show that SNX4 regulates BACE1 trafficking. Our findings suggest novel therapeutic implications of modulating SNX4 to regulate BACE1-mediated ß-processing of APP and subsequent Aß generation.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/metabolismo
Ácido Aspártico Endopeptidases/metabolismo
Nexinas de Classificação/metabolismo
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Precursor de Proteína beta-Amiloide/genética
Precursor de Proteína beta-Amiloide/metabolismo
Animais
Encéfalo/metabolismo
Encéfalo/patologia
Membrana Celular/metabolismo
Membrana Celular/patologia
Células HEK293
Células HeLa
Seres Humanos
Masculino
Camundongos Transgênicos
Neurônios/metabolismo
Neurônios/patologia
Presenilina-1/genética
Presenilina-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APP protein, human); 0 (Amyloid beta-Protein Precursor); 0 (PSEN1 protein, human); 0 (Presenilin-1); 0 (SNX4 protein, human); 0 (SNX4 protein, mouse); 0 (Sorting Nexins); EC 3.4.- (Amyloid Precursor Protein Secretases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.46 (BACE1 protein, human); EC 3.4.23.46 (Bace1 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170123
[St] Status:MEDLINE
[do] DOI:10.1186/s13195-016-0232-8



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