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[PMID]:29371662
[Au] Autor:Bohl TE; Shi K; Lee JK; Aihara H
[Ad] Endereço:Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Twin Cities, Minneapolis, MN, 55455, USA.
[Ti] Título:Crystal structure of lipid A disaccharide synthase LpxB from Escherichia coli.
[So] Source:Nat Commun;9(1):377, 2018 01 25.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Most Gram-negative bacteria are surrounded by a glycolipid called lipopolysaccharide (LPS), which forms a barrier to hydrophobic toxins and, in pathogenic bacteria, is a virulence factor. During LPS biosynthesis, a membrane-associated glycosyltransferase (LpxB) forms a tetra-acylated disaccharide that is further acylated to form the membrane anchor moiety of LPS. Here we solve the structure of a soluble and catalytically competent LpxB by X-ray crystallography. The structure reveals that LpxB has a glycosyltransferase-B family fold but with a highly intertwined, C-terminally swapped dimer comprising four domains. We identify key catalytic residues with a product, UDP, bound in the active site, as well as clusters of hydrophobic residues that likely mediate productive membrane association or capture of lipidic substrates. These studies provide the basis for rational design of antibiotics targeting a crucial step in LPS biosynthesis.
[Mh] Termos MeSH primário: Escherichia coli/enzimologia
Lipopolissacarídeos/química
N-Acetilglucosaminiltransferases/química
Difosfato de Uridina/química
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Carboidratos Epimerases/química
Carboidratos Epimerases/genética
Carboidratos Epimerases/metabolismo
Domínio Catalítico
Clonagem Molecular
Cristalografia por Raios X
Escherichia coli/genética
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Interações Hidrofóbicas e Hidrofílicas
Lipopolissacarídeos/biossíntese
Modelos Moleculares
N-Acetilglucosaminiltransferases/genética
N-Acetilglucosaminiltransferases/metabolismo
Ligação Proteica
Dobramento de Proteína
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Estrutura Secundária de Proteína
Homologia Estrutural de Proteína
Especificidade por Substrato
Thermus thermophilus/enzimologia
Thermus thermophilus/genética
Difosfato de Uridina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Lipopolysaccharides); 58-98-0 (Uridine Diphosphate); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.182 (lipid A disaccharide synthase); EC 5.1.3.- (Carbohydrate Epimerases); EC 5.1.3.14 (UDP acetylglucosamine-2-epimerase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02712-9


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[PMID]:29244071
[Au] Autor:Muter J; Alam MT; Vrljicak P; Barros FSV; Ruane PT; Ewington LJ; Aplin JD; Westwood M; Brosens JJ
[Ad] Endereço:Division of Biomedical Sciences, Clinical Science Research Laboratories, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
[Ti] Título:The Glycosyltransferase EOGT Regulates Adropin Expression in Decidualizing Human Endometrium.
[So] Source:Endocrinology;159(2):994-1004, 2018 02 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In pregnancy, resistance of endometrial decidual cells to stress signals is critical for the integrity of the fetomaternal interface and, by extension, survival of the conceptus. O-GlcNAcylation is an essential posttranslational modification that links glucose sensing to cellular stress resistance. Unexpectedly, decidualization of primary endometrial stromal cells (EnSCs) was associated with a 60% reduction in O-linked ß-N-acetylglucosamine (O-GlcNAc)‒modified proteins, reflecting downregulation of the enzyme that adds O-GlcNAc to substrates (O-GlcNAc transferase; OGT) but not the enzyme that removes the modification (O-GlcNAcase). Notably, epidermal growth factor domain-specific O-linked GlcNAc transferase (EOGT), an endoplasmic reticulum-specific OGT that modifies a limited number of secreted and membrane proteins, was markedly induced in differentiating EnSCs. Knockdown of EOGT perturbed a network of decidual genes involved in multiple cellular functions. The most downregulated gene upon EOGT knockdown in decidualizing cells was the energy homeostasis-associated gene (ENHO), which encodes adropin, a metabolic hormone involved in energy homeostasis and glucose and fatty acid metabolism. Analysis of midluteal endometrial biopsies revealed an inverse correlation between endometrial EOGT and ENHO expression and body mass index. Taken together, our findings revealed that obesity impairs the EOGT-adropin axis in decidual cells, which in turn points toward a mechanistic link between metabolic disorders and adverse pregnancy outcome.
[Mh] Termos MeSH primário: Proteínas Sanguíneas/genética
Implantação do Embrião/genética
Endométrio/metabolismo
N-Acetilglucosaminiltransferases/fisiologia
Peptídeos/genética
[Mh] Termos MeSH secundário: Biópsia
Proteínas Sanguíneas/metabolismo
Índice de Massa Corporal
Células Cultivadas
Endométrio/enzimologia
Endométrio/patologia
Feminino
Regulação da Expressão Gênica
Seres Humanos
Infertilidade Feminina/complicações
Infertilidade Feminina/genética
Infertilidade Feminina/patologia
Obesidade/complicações
Obesidade/genética
Obesidade/patologia
Peptídeos/metabolismo
Gravidez
Complicações na Gravidez/genética
Complicações na Gravidez/patologia
Resultado da Gravidez/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blood Proteins); 0 (Enho protein, human); 0 (Peptides); EC 2.4.1.- (EOGT protein, human); EC 2.4.1.- (N-Acetylglucosaminyltransferases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-03064


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[PMID]:29253568
[Au] Autor:Murata K; Morino K; Ida S; Ohashi N; Lemecha M; Park SY; Ishikado A; Kume S; Choi CS; Sekine O; Ugi S; Maegawa H
[Ad] Endereço:Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu, Shiga, 520-2192, Japan.
[Ti] Título:Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle.
[So] Source:Biochem Biophys Res Commun;495(2):2098-2104, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine (GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated. In this study, we created skeletal muscle-specific Ogt knockout (Ogt-MKO) mice and analyzed their glucose metabolism. During an intraperitoneal glucose tolerance test, blood glucose was slightly lower in Ogt-MKO mice than in control Ogt-flox mice. High fat diet-induced obesity and insulin resistance were reversed in Ogt-MKO mice. In addition, 12-month-old Ogt-MKO mice had lower adipose and body mass. A single bout of exercise significantly reduced blood glucose in Ogt-MKO mice, probably because of higher AMP-activated protein kinase α (AMPKα) protein expression. Furthermore, intraperitoneal injection of 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, resulted in a more marked decrease in blood glucose levels in Ogt-MKO mice than in controls. Finally, Ogt knockdown by siRNA in C2C12 myotubes significantly increased protein expression of AMPKα, glucose uptake and oxidation. In conclusion, loss of O-GlcNAcylation facilitates glucose utilization in skeletal muscle, potentially through AMPK activation. The inhibition of O-GlcNAcylation in skeletal muscle may have an anti-diabetic effect, through an enhancement of glucose utilization during exercise.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/metabolismo
Glucose/metabolismo
Contração Muscular/fisiologia
Músculo Esquelético/fisiologia
N-Acetilglucosaminiltransferases/metabolismo
Esforço Físico/fisiologia
[Mh] Termos MeSH secundário: Acilação/fisiologia
Animais
Glicemia/metabolismo
Ativação Enzimática/fisiologia
Regulação Enzimológica da Expressão Gênica/fisiologia
Masculino
Camundongos
Camundongos Knockout
Condicionamento Físico Animal/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blood Glucose); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (O-GlcNAc transferase); EC 2.7.11.31 (AMP-Activated Protein Kinases); IY9XDZ35W2 (Glucose)
[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:171219
[St] Status:MEDLINE


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[PMID]:29320543
[Au] Autor:Blaeser A; Awano H; Lu P; Lu QL
[Ad] Endereço:McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas HealthCare System, Charlotte, North Carolina, United States of America.
[Ti] Título:Distinct expression of functionally glycosylated alpha-dystroglycan in muscle and non-muscle tissues of FKRP mutant mice.
[So] Source:PLoS One;13(1):e0191016, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The glycosylation of alpha-dystroglycan (α-DG) is crucial in maintaining muscle cell membrane integrity. Dystroglycanopathies are identified by the loss of this glycosylation leading to a breakdown of muscle cell membrane integrity and eventual degeneration. However, a small portion of fibers expressing functionally glycosylated α-DG (F-α-DG) (revertant fibers, RF) have been identified. These fibers are generally small in size, centrally nucleated and linked to regenerating fibers. Examination of different muscles have shown various levels of RFs but it is unclear the extent of which they are present. Here we do a body-wide examination of muscles from the FKRP-P448L mutant mouse for the prevalence of RFs. We have identified great variation in the distribution of RF in different muscles and tissues. Triceps shows a large increase in RFs and together with centrally nucleated fibers whereas the pectoralis shows a reduction in revertant but increase in centrally nucleated fibers from 6 weeks to 6 months of age. We have also identified that the sciatic nerve with near normal levels of F-α-DG in the P448Lneo- mouse with reduced levels in the P448Lneo+ and absent in LARGEmyd. The salivary gland of LARGEmyd mice expresses high levels of F-α-DG. Interestingly the same glands in the P448Lneo-and to a lesser degree in P448Lneo+ also maintain considerable amount of F-α-DG, indicating the non-proliferating epithelial cells have a molecular setting permitting glycosylation.
[Mh] Termos MeSH primário: Distroglicanas/metabolismo
Músculo Esquelético/metabolismo
Mutação
N-Acetilglucosaminiltransferases/fisiologia
Nervos Periféricos/metabolismo
Proteínas/fisiologia
Glândulas Salivares/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Distroglicanas/genética
Glicosilação
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fibras Musculares Esqueléticas/metabolismo
Fibras Musculares Esqueléticas/patologia
Músculo Esquelético/patologia
Nervos Periféricos/patologia
Regeneração/fisiologia
Glândulas Salivares/patologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dag1 protein, mouse); 0 (Fkrp protein, mouse); 0 (Proteins); 146888-27-9 (Dystroglycans); EC 2.4.1.- (Large protein, mouse); EC 2.4.1.- (N-Acetylglucosaminyltransferases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191016


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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]:28450392
[Au] Autor:Wu D; Zhao L; Feng Z; Yu C; Ding J; Wang L; Wang F; Liu D; Zhu H; Xing F; Conaway JW; Conaway RC; Cai Y; Jin J
[Ad] Endereço:From the School of Life Sciences.
[Ti] Título:-Linked -acetylglucosamine transferase 1 regulates global histone H4 acetylation via stabilization of the nonspecific lethal protein NSL3.
[So] Source:J Biol Chem;292(24):10014-10025, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The human males absent on the first (MOF)-containing histone acetyltransferase nonspecific lethal (NSL) complex comprises nine subunits including the -linked -acetylglucosamine ( -GlcNAc) transferase, isoform 1 (OGT1). However, whether the -GlcNAc transferase activity of OGT1 controls histone acetyltransferase activity of the NSL complex and whether OGT1 physically interacts with the other NSL complex subunits remain unclear. Here, we demonstrate that OGT1 regulates the activity of the NSL complex by mainly acetylating histone H4 Lys-16, Lys-5, and Lys-8 via -GlcNAcylation and stabilization of the NSL complex subunit NSL3. Knocking down or overexpressing OGT1 in human cells remarkably affected the global acetylation of histone H4 residues Lys-16, Lys-5, and Lys-8. Because OGT1 is a subunit of the NSL complex, we also investigated the function of OGT1 in this complex. Co-transfection/co-immunoprecipitation experiments combined with -GlcNAc transferase assays confirmed that OGT1 specifically binds to and -GlcNAcylates NSL3. In addition, wheat germ agglutinin affinity purification verified the occurrence of -GlcNAc modification on NSL3 in cells. Moreover, -GlcNAcylation of NSL3 by wild-type OGT1 (OGT1-WT) stabilized NSL3. This stabilization was lost after co-transfection of NSL3 with an OGT1 mutant, OGT1 , that lacks -GlcNAc transferase activity. Furthermore, stabilization of NSL3 by OGT1-WT significantly increased the global acetylation levels of H4 Lys-5, Lys-8, and Lys-16 in cells. These results suggest that OGT1 regulates the activity of the NSL complex by stabilizing NSL3.
[Mh] Termos MeSH primário: Histona Acetiltransferases/metabolismo
Histonas/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Proteínas Nucleares/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Acetilação
Substituição de Aminoácidos
Animais
Células HEK293
Células HeLa
Histona Acetiltransferases/antagonistas & inibidores
Histona Acetiltransferases/química
Histona Acetiltransferases/genética
Seres Humanos
Isoenzimas/química
Isoenzimas/genética
Isoenzimas/metabolismo
N-Acetilglucosaminiltransferases/antagonistas & inibidores
N-Acetilglucosaminiltransferases/química
N-Acetilglucosaminiltransferases/genética
Proteínas Nucleares/antagonistas & inibidores
Proteínas Nucleares/química
Proteínas Nucleares/genética
Mutação Puntual
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Estabilidade Proteica
Subunidades Proteicas/química
Subunidades Proteicas/genética
Subunidades Proteicas/metabolismo
Interferência de RNA
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Células Sf9
Spodoptera
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Histones); 0 (Isoenzymes); 0 (KANSL3 protein, human); 0 (Nuclear Proteins); 0 (Protein Isoforms); 0 (Protein Subunits); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); EC 2.3.1.48 (Histone Acetyltransferases); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171228
[Lr] Data última revisão:
171228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.781401


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[PMID]:28742148
[Au] Autor:Groussaud D; Khair M; Tollenaere AI; Waast L; Kuo MS; Mangeney M; Martella C; Fardini Y; Coste S; Souidi M; Benit L; Pique C; Issad T
[Ad] Endereço:INSERM, U1016, Institut Cochin, Paris, France.
[Ti] Título:Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription.
[So] Source:PLoS Pathog;13(7):e1006518, 2017 Jul.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The viral Tax oncoprotein plays a key role in both Human T-cell lymphotropic virus type 1 (HTLV-1)-replication and HTLV-1-associated pathologies, notably adult T-cell leukemia. Tax governs the transcription from the viral 5'LTR, enhancing thereby its own expression, via the recruitment of dimers of phosphorylated CREB to cAMP-response elements located within the U3 region (vCRE). In addition to phosphorylation, CREB is also the target of O-GlcNAcylation, another reversible post-translational modification involved in a wide range of diseases, including cancers. O-GlcNAcylation consists in the addition of O-linked-N-acetylglucosamine (O-GlcNAc) on Serine or Threonine residues, a process controlled by two enzymes: O-GlcNAc transferase (OGT), which transfers O-GlcNAc on proteins, and O-GlcNAcase (OGA), which removes it. In this study, we investigated the status of O-GlcNAcylation enzymes in HTLV-1-transformed T cells. We found that OGA mRNA and protein expression levels are increased in HTLV-1-transformed T cells as compared to control T cell lines while OGT expression is unchanged. However, higher OGA production coincides with a reduction in OGA specific activity, showing that HTLV-1-transformed T cells produce high level of a less active form of OGA. Introducing Tax into HEK-293T cells or Tax-negative HTLV-1-transformed TL-om1 T cells is sufficient to inhibit OGA activity and increase total O-GlcNAcylation, without any change in OGT activity. Furthermore, Tax interacts with the OGT/OGA complex and inhibits the activity of OGT-bound OGA. Pharmacological inhibition of OGA increases CREB O-GlcNAcylation as well as HTLV-1-LTR transactivation by Tax and CREB recruitment to the LTR. Moreover, overexpression of wild-type CREB but not a CREB protein mutated on a previously described O-GlcNAcylation site enhances Tax-mediated LTR transactivation. Finally, both OGT and OGA are recruited to the LTR. These findings reveal the interplay between Tax and the O-GlcNAcylation pathway and identify new key molecular actors involved in the assembly of the Tax-dependent transactivation complex.
[Mh] Termos MeSH primário: Produtos do Gene tax/metabolismo
Infecções por HTLV-I/virologia
Vírus 1 Linfotrópico T Humano/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Linfócitos T/virologia
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
Regulação Viral da Expressão Gênica
Produtos do Gene tax/genética
Infecções por HTLV-I/enzimologia
Infecções por HTLV-I/genética
Infecções por HTLV-I/metabolismo
Interações Hospedeiro-Patógeno
Vírus 1 Linfotrópico T Humano/genética
Seres Humanos
N-Acetilglucosaminiltransferases/genética
Processamento de Proteína Pós-Traducional
Linfócitos T/enzimologia
Linfócitos T/metabolismo
Transcrição Genética
beta-N-Acetil-Hexosaminidases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic AMP Response Element-Binding Protein); 0 (Gene Products, tax); 0 (tax protein, Human T-lymphotrophic virus 1); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (O-GlcNAc transferase); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006518


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[PMID]:28745318
[Au] Autor:Ye J; Wei X; Shang Y; Pan Q; Yang M; Tian Y; He Y; Peng Z; Chen L; Chen W; Wang R
[Ad] Endereço:Department of Gastroenterology, Institute of Gastroenterology of PLA, Southwest Hospital, Third Military Medical University, Chongqing, China.
[Ti] Título:Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity.
[So] Source:Oncogene;36(46):6391-6407, 2017 Nov 16.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The attachment of cell-surface carbohydrates to proteins mediated by the amino acids serine or threonine (O-glycan) is involved in tumor metastasis; the roles of O-glycans vary depending on their structure, but the detailed mechanisms by which O-glycans trigger signaling to control tumor metastasis are largely unknown. In this study, we found that the reduced expression of core 3 synthase correlated with metastasis to lymph nodes and distant organs, resulting in poor prognosis for colorectal cancer (CRC) patients. Mechanically, we revealed that mucin-type core 3 O-glycan was synthesized at the membrane-tethered MUC1 N terminus because of core 3 synthase expression in colon cancer cells. This further inhibited the translocation of MUC1-C to the nucleus, initiated p53 gene transcription that was dependent on the inhibition of MUC1-C nucleus translocation, activated p53-mediated miR-200c expression and resulted in mesenchymal-epithelial transition (MET). Inhibition of MUC1 via small interfering RNA (siRNA) in re-expressed core 3 synthase colon cancer cells further inhibited MUC1-C nucleus translocation, increased p53 and miR-200c expression, and enhanced MET. However, inhibition of p53 via siRNA or miR-200c via miR-200c inhibitor in re-expressed core 3 synthase colon cancer cells promoted the epithelial-mesenchymal transition (EMT) in a reversible manner. Core 3 synthase mRNA levels and the p53 mRNA levels or miR-200c levels in the colon cancerous samples were positively correlated. Our findings suggest a novel mechanism linking mucin-type core 3 O-glycan to the EMT-MET plasticity of CRC cells via MUC1/p53/miR-200c-dependent signaling cascade and shed light on therapeutic strategies to treat this malignancy.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
Transição Epitelial-Mesenquimal/genética
MicroRNAs/genética
Mucina-1/genética
Polissacarídeos/metabolismo
Proteína Supressora de Tumor p53/genética
[Mh] Termos MeSH secundário: Western Blotting
Células CACO-2
Linhagem Celular Tumoral
Núcleo Celular/metabolismo
Neoplasias Colorretais/metabolismo
Neoplasias Colorretais/patologia
Regulação Neoplásica da Expressão Gênica
Células HCT116
Células HT29
Seres Humanos
MicroRNAs/metabolismo
Mucina-1/metabolismo
Mucinas/metabolismo
N-Acetilglucosaminiltransferases/genética
N-Acetilglucosaminiltransferases/metabolismo
Transporte Proteico
Interferência de RNA
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN200 microRNA, human); 0 (MUC1 protein, human); 0 (MicroRNAs); 0 (Mucin-1); 0 (Mucins); 0 (Polysaccharides); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (UDP-GlcNAc GalNAc-peptide beta1,3-N-acetylglucosaminyltransferase)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171201
[Lr] Data última revisão:
171201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2017.241


  9 / 2696 MEDLINE  
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[PMID]:28903979
[Au] Autor:Ruan HB; Ma Y; Torres S; Zhang B; Feriod C; Heck RM; Qian K; Fu M; Li X; Nathanson MH; Bennett AM; Nie Y; Ehrlich BE; Yang X
[Ad] Endereço:Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
[Ti] Título:Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation.
[So] Source:Genes Dev;31(16):1655-1665, 2017 Aug 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation. These findings uncover a signaling cascade by which starvation promotes autophagy through OGT phosphorylation and establish the importance of O-GlcNAc signaling in coupling liver autophagy to nutrient homeostasis.
[Mh] Termos MeSH primário: Autofagia
Sinalização do Cálcio
Fígado/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Fenômenos Fisiológicos da Nutrição
[Mh] Termos MeSH secundário: Adaptação Biológica
Animais
Proteína 5 Relacionada à Autofagia/fisiologia
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Células Cultivadas
Glucagon/farmacologia
Células HEK293
Células HeLa
Seres Humanos
Receptores de Inositol 1,4,5-Trifosfato/metabolismo
Fígado/efeitos dos fármacos
Fígado/enzimologia
Camundongos Endogâmicos C57BL
N-Acetilglucosaminiltransferases/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Atg5 protein, mouse); 0 (Autophagy-Related Protein 5); 0 (Inositol 1,4,5-Trisphosphate Receptors); 9007-92-5 (Glucagon); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171029
[Lr] Data última revisão:
171029
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1101/gad.305441.117


  10 / 2696 MEDLINE  
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[PMID]:28886091
[Au] Autor:Britto-Borges T; Barton GJ
[Ad] Endereço:Division of Computational Biology, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
[Ti] Título:A study of the structural properties of sites modified by the O-linked 6-N-acetylglucosamine transferase.
[So] Source:PLoS One;12(9):e0184405, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein O-GlcNAcylation (O-GlcNAc) is an essential post-translational modification (PTM) in higher eukaryotes. The O-linked ß-N-acetylglucosamine transferase (OGT), targets specific Serines and Threonines (S/T) in intracellular proteins. However, unlike phosphorylation, fewer than 25% of known O-GlcNAc sites match a clear sequence pattern. Accordingly, the three-dimensional structures of O-GlcNAc sites were characterised to investigate the role of structure in molecular recognition. From 1,584 O-GlcNAc sites in 620 proteins, 143 were mapped to protein structures determined by X-ray crystallography. The modified S/T were 1.7 times more likely to be annotated in the REM465 field which defines missing residues in a protein structure, while 7 O-GlcNAc sites were solvent inaccessible and unlikely to be targeted by OGT. 132 sites with complete backbone atoms clustered into 10 groups, but these were indistinguishable from clusters from unmodified S/T. This suggests there is no prevalent three-dimensional motif for OGT recognition. Predicted features from the 620 proteins were compared to unmodified S/T in O-GlcNAcylated proteins and globular proteins. The Jpred4 predicted secondary structure shows that modified S/T were more likely to be coils. 5/6 methods to predict intrinsic disorder indicated O-GlcNAcylated S/T to be significantly more disordered than unmodified S/T. Although the analysis did not find a pattern in the site three-dimensional structure, it revealed the residues around the modification site are likely to be disordered and suggests a potential role of secondary structure elements in OGT site recognition.
[Mh] Termos MeSH primário: Modelos Moleculares
N-Acetilglucosaminiltransferases/química
Conformação Proteica
[Mh] Termos MeSH secundário: Acetilglucosamina/genética
Acetilglucosamina/metabolismo
Sítios de Ligação
N-Acetilglucosaminiltransferases/metabolismo
Ligação Proteica
Processamento de Proteína Pós-Traducional
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.4.1.- (N-Acetylglucosaminyltransferases); V956696549 (Acetylglucosamine)
[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:170909
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184405



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