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Po-Han Chen, Jen-Tsan Chi, Michael Boyce
In metazoans, thousands of intracellular proteins are modified with O-linked β-N-acetylglucosamine (O-GlcNAc) in response to a wide range of stimuli and stresses. In particular, a complex and evolutionarily conserved interplay between O-GlcNAcylation and oxidative stress has emerged in recent years. Here, we review the current literature on the connections between O-GlcNAc and oxidative stress, with a particular emphasis on major signaling pathways, such as KEAP1/NRF2, FOXO, NFκB, p53 and cell metabolism...
March 14, 2018: Glycobiology
Cangzhi Jia, Yun Zuo
Protein O-GlcNAcylation on serine and threonine residues is a significant posttranslational modification. Experimental techniques can uncover only a small portion of O-GlcNAcylation sites. Several computational algorithms have been proposed as necessary auxiliary tools to identify potential O-GlcNAcylation sites. This chapter discusses the metrics and procedures used to assess prediction tools and surveys six computational tools for the prediction of protein O-GlcNAcylation sites. Analyses of these tools using an independent test dataset indicated the advantages and disadvantages of the six existing prediction methods...
2018: Methods in Molecular Biology
Peng Yu, Lili Hu, Jinyan Xie, Sisi Chen, Lin Huang, Zixuan Xu, Xiao Liu, Qiongqiong Zhou, Ping Yuan, Xia Yan, Jiejin Jin, Yang Shen, Wengen Zhu, Linghua Fu, Qi Chen, Jianhua Yu, Jianxin Hu, Qing Cao, Rong Wan, Kui Hong
BACKGROUND: Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias...
February 27, 2018: International Journal of Cardiology
Hao Shi, Alexander Munk, Thomas S Nielsen, Morgan R Daughtry, Louise Larsson, Shize Li, Kasper F Høyer, Hannah W Geisler, Karolina Sulek, Rasmus Kjøbsted, Taylor Fisher, Marianne M Andersen, Zhengxing Shen, Ulrik K Hansen, Eric M England, Zhiyong Cheng, Kurt Højlund, Jørgen F P Wojtaszewski, Xiaoyong Yang, Matthew W Hulver, Richard F Helm, Jonas T Treebak, David E Gerrard
OBJECTIVE: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. METHODS: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry...
February 24, 2018: Molecular Metabolism
Ninon Very, Agata Steenackers, Caroline Dubuquoy, Jeanne Vermuse, Laurent Dubuquoy, Tony Lefebvre, Ikram El Yazidi-Belkoura
The hexosamine biosynthetic pathway (HBP) integrates glucose, amino acids, fatty acids and nucleotides metabolisms for uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) synthesis. UDP-GlcNAc is the nucleotide sugar donor for O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) processes. O-GlcNAc transferase (OGT) is the enzyme which transfers the N-acetylglucosamine (O-GlcNAc) residue onto target proteins. Several studies previously showed that glucose metabolism dysregulations associated with obesity, diabetes or cancer correlated with an increase of OGT expression and global O-GlcNAcylation levels...
March 9, 2018: Journal of Bioenergetics and Biomembranes
Pedro Merino, Mattia Ghirardello, Daniela Perrone, Nicola Chinaglia, David Sadaba, Ignacio Delso, Tomas Tejero, Elena Marchesi, Marco Fogagnolo, Karim Rafie, Daan M F van Aalten
A series of glycomimetics of UDP-GlcNAc in which the β-phosphate has been replaced by either an alkyl chain or a triazolyl ring and the sugar moiety has been replaced by a pyrrolidine ring have been synthesized by using different click-chemistry procedures. Their affinity for human O-GlcNAc transferase (hOGT) has been evaluated and both spectroscopically and computationally studied. The binding epitopes of the best ligands have been determined in solution using saturation transfer difference (STD) NMR spectroscopy...
March 7, 2018: Chemistry: a European Journal
Heather J Tarbet, Lee Dolat, Timothy J Smith, Brett M Condon, E Timothy O'Brien, Raphael H Valdivia, Michael Boyce
Intermediate filaments (IF) are a major component of the metazoan cytoskeleton and are essential for normal cell morphology, motility, and signal transduction. Dysregulation of IFs causes a wide range of human diseases, including skin disorders, cardiomyopathies, lipodystrophy, and neuropathy. Despite this pathophysiological significance, how cells regulate IF structure, dynamics, and function remains poorly understood. Here, we show that site-specific modification of the prototypical IF protein vimentin with O-linked β- N -acetylglucosamine (O-GlcNAc) mediates its homotypic protein-protein interactions and is required in human cells for IF morphology and cell migration...
March 7, 2018: ELife
Zebulon Levine, Chenguang Fan, Michael S Melicher, Marina Orman, Tania Benjamin, Suzanne Walker
The essential mammalian enzyme O-GlcNAc Transferase (OGT) is uniquely responsible for transferring N-acetylglucosamine to over a thousand nuclear and cytoplasmic proteins, yet there is no known consensus sequence and it remains unclear how OGT recognizes its substrates. To address this question, we developed a protein microarray assay that chemoenzymatically labels de novo sites of glycosylation with biotin, allowing us to simultaneously assess OGT activity across >6000 human proteins. With this assay we examined the contribution to substrate selection of a conserved asparagine ladder within the lumen of OGT's superhelical tetratricopeptide repeat (TPR) domain...
February 27, 2018: Journal of the American Chemical Society
Yanping Zhu, Xiaoyang Shan, Farzaneh Safarpour, Nancy Erro Go, Nancy Li, Alice Shan, Mina Huang, Matthew Deen, Viktor Holicek, Roger Ashmus, Zarina Madden, Sharon Gorski, Michael Silverman, David J Vocadlo
The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer Disease (AD) mouse models manifesting either tau or amyloid pathology...
February 20, 2018: ACS Chemical Neuroscience
Fangfang Duan, Hao Wu, Dongwei Jia, Weicheng Wu, Shifang Ren, Lan Wang, Shushu Song, Xinying Guo, Fenglin Liu, Yuanyuan Ruan, Jianxin Gu
BACKGROUND & AIMS: Aberrant oncogenic mRNA translation and protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal RACK1 promoted the chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis...
February 14, 2018: Journal of Hepatology
Min Jun Kim, Mee Young Choi, Dong Hoon Lee, Gu Seob Roh, Hyun Joon Kim, Sang Soo Kang, Gyeong Jae Cho, Yoon Sook Kim, Wan Sung Choi
O-linked N-acetylglucosamine transferase (OGT) expression is increased in various cancer types, indicating the potential importance of O-GlcNAcylation in tumorigenesis. Secretory clusterin (sCLU) is involved in cancer cell proliferation and drug resistance, and recently, liver X receptors (LXRs) and sterol response element binding protein-1 (SREBP-1) were reported to regulate sCLU transcription. Here, we found that sCLU is significantly increased in cervical cancer cell lines, which have higher expression levels of O-GlcNAc and OGT than keratinocytes...
January 12, 2018: Oncotarget
Cangzhi Jia, Yun Zuo, Quan Zou, John Hancock
Motivation: Protein O-GlcNAcylation (O-GlcNAc) is an important post-translational modification of serine (S)/threonine (T) residues that involves multiple molecular and cellular processes. Recent studies have suggested that abnormal O-G1cNAcylation causes many diseases, such as cancer and various neurodegenerative diseases. With the available protein O-G1cNAcylation sites experimentally verified, it is highly desired to develop automated methods to rapidly and effectively identify O-G1cNAcylation sites...
February 6, 2018: Bioinformatics
Miranda Machacek, Chad Slawson, Patrick E Fields
The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4+ T cells are essential for the adaptive immune response leading to the eradication of specific pathogens. However, when T cells are inappropriately over-active, they can drive autoimmunity, allergic disease, and chronic inflammation. The mechanisms by which metabolic changes influence function in CD4+ T cells are not fully understood. The post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine), dynamically cycles on and off of intracellular proteins as cells respond to their environment and flux through metabolic pathways changes...
February 6, 2018: Journal of Bioenergetics and Biomembranes
Hannah M Brown, Ella S Green, Tiffany C Y Tan, Macarena B Gonzalez, Alice R Rumbold, M Louise Hull, Robert J Norman, Nicolle H Packer, Sarah A Robertson, Jeremy G Thompson
Diabetes has been linked with impaired fertility but the underlying mechanisms are not well defined. Here we use a streptozotocin-induced diabetes mouse model to investigate the cellular and biochemical changes in conceptus and maternal tissues that accompany hyperglycaemia. We report that streptozotocin treatment before conception induces profound intra-cellular protein β-O-glycosylation (O-GlcNAc) in the oviduct and uterine epithelium, prominent in early pregnancy. Diabetic mice have impaired blastocyst development and reduced embryo implantation rates, and delayed mid-gestation growth and development...
February 1, 2018: Scientific Reports
Shani Ben Harosh-Davidovich, Isam Khalaila
O-GlcNAcylation, the addition of β-N-acetylglucosamine (O-GlcNAc) moiety to Ser/Thr residues, is a sensor of the cell metabolic state. Cancer diseases such as colon, lung and breast cancer, possess deregulated O-GlcNAcylation. Studies during the last decade revealed that O-GlcNAcylation is implicated in cancer tumorigenesis and proliferation. The Wnt/β-catenin signaling pathway and cadherin-mediated adhesion are also implicated in epithelial-mesenchymal transition (EMT), a key cellular process in invasion and cancer metastasis...
January 30, 2018: Experimental Cell Research
Abdullah Hoter, Mahdi Amiri, Abdelbary Prince, Hassan Amer, Mohamad Warda, Hassan Y Naim
Increased expression of heat shock proteins (HSPs) following heat stress or other stress conditions is a common physiological response in almost all living organisms. Modification of cytosolic proteins including HSPs by O-GlcNAc has been shown to enhance their capabilities for counteracting lethal levels of cellular stress. Since HSPs are key players in stress resistance and protein homeostasis, we aimed to analyze their forms at the cellular and molecular level using camel and human HSPs as models for efficient and moderate thermotolerant mammals, respectively...
January 30, 2018: International Journal of Molecular Sciences
Tom Grunert, Dijana Jovanovic, Wanchat Sirisarn, Sophia Johler, Christopher Weidenmaier, Monika Ehling-Schulz, Guoqing Xia
Surface carbohydrate moieties are essential for bacterial communication, phage-bacteria and host-pathogen interaction. Most Staphylococcus aureus produce polyribitolphosphate type Wall teichoic acids (WTAs) substituted with α- and/or β-O-linked N-acetyl-glucosamine (α-/β-O-GlcNAc) residues. GlcNAc modifications have attracted particular interest, as they were shown to govern staphylococcal adhesion to host cells, to promote phage susceptibility conferring beta-lactam resistance and are an important target for antimicrobial agents and vaccines...
January 30, 2018: Scientific Reports
Zafer Gurel, Nader Sheibani
The incidence of diabetes continues to rise among all ages and ethnic groups worldwide. Diabetic retinopathy (DR) is a complication of diabetes that affects the retinal neurovasculature causing serious vision problems, including blindness. Its pathogenesis and severity is directly linked to the chronic exposure to high glucose conditions. No treatments are currently available to stop the development and progression of DR. To develop new and effective therapeutic approaches, it is critical to better understand how hyperglycemia contributes to the pathogenesis of DR at the cellular and molecular levels...
January 31, 2018: Clinical Science (1979-)
Christina M Woo, Peder J Lund, Andrew C Huang, Mark M Davis, Carolyn R Bertozzi, Sharon Pitteri
Post-translational modifications (PTMs) on proteins often function to regulate signaling cascades, with the activation of T cells during an adaptive immune response being a classic example.  Mounting evidence indicates that the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc), the only mammalian glycan found on nuclear and cytoplasmic proteins, helps regulate T cell activation.  Yet, a mechanistic understanding of how O-GlcNAc functions in T cell activation remains elusive, partly because of the difficulties in mapping and quantifying O-GlcNAc sites...
January 19, 2018: Molecular & Cellular Proteomics: MCP
Caroline Smet-Nocca, Adeline Page, François-Xavier Cantrelle, Eleni Nikolakaki, Isabelle Landrieu, Thomas Giannakouros
Lamin B Receptor (LBR) is an integral protein of the interphase inner nuclear membrane that is implicated in chromatin anchorage to the nuclear envelope. Phosphorylation of a stretch of arginine-serine (RS) dipeptides in the amino-terminal nucleoplasmic domain of LBR regulates the interactions of the receptor with other nuclear proteins, DNA and RNA and thus modulates tethering of heterochromatin to the nuclear envelope. While phosphorylation has been extensively studied, very little is known about other post-translational modifications of the protein...
January 11, 2018: Biochimica et Biophysica Acta
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