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Mitochondrion Jul 2022O-GlcNAcylation, a ubiquitous post-translational modification, rapidly modulates protein activity through the reversible addition and removal of O-GlcNAc groups from... (Review)
Review
O-GlcNAcylation, a ubiquitous post-translational modification, rapidly modulates protein activity through the reversible addition and removal of O-GlcNAc groups from serine or threonine residues in target proteins, and is involved in multiple metabolic pathways. With the discovery of enzymes and substrates for O-GlcNAc cycling in mitochondria, mitochondrial O-GlcNAc modification and its regulatory role in mitochondrial function deserve extensive attention. Adaptive regulation of the O-GlcNAc cycling in response to energy perturbations is demonstrated to be important in maintaining mitochondrial homeostasis. Dysregulation of O-GlcNAcylation in mitochondria has been associated with various mitochondrial dysfunctions, such as abnormal mitochondrial dynamics, reduced mitochondrial biosynthesis, disruption of the electron transport chain, oxidative stress and the calcium paradox, as well as activation of mitochondrial apoptosis pathways. Here, we outline the current understanding of O-GlcNAc modification in mitochondria and the key discovery of O-GlcNAcylation in regulating mitochondrial network homeostasis. This review will provide insights into targeting mitochondrial O-GlcNAcylation, as well as the mechanisms linking mitochondrial dysfunction and disease.
Topics: Acetylglucosamine; Calcium; Homeostasis; Mitochondria; Protein Processing, Post-Translational
PubMed: 35513218
DOI: 10.1016/j.mito.2022.04.007 -
Glycoconjugate Journal Aug 2018Bisecting GlcNAc, a branch structure in N-glycan, has unique functions and is involved in several diseases including Alzheimer's disease (AD). In this review, we provide... (Review)
Review
Bisecting GlcNAc, a branch structure in N-glycan, has unique functions and is involved in several diseases including Alzheimer's disease (AD). In this review, we provide an overview of the biosynthesis of bisecting GlcNAc and its physiological and pathological functions, particularly in the nervous system where bisecting GlcNAc is most highly expressed. The biosynthetic enzyme of bisecting GlcNAc is N-acetylglucosaminyltransferase-III (GnT-III). Overexpression, knockdown, and knockout of GnT-III have so far revealed various functions of bisecting GlcNAc, which are mediated by regulating the functions of key carrier proteins. GnT-III-deficient AD model mice showed reduced amyloid-β (Aβ) accumulation in the brain by suppressing the function of a key Aβ-generating enzyme, β-site APP-cleaving enzyme-1 (BACE1), and greatly improved AD pathology. Altered BACE1 subcellular localization in GnT-III-deficient cells, from early endosomes to lysosomes, suggests that bisecting GlcNAc serves as a trafficking tag for the movement of modified proteins to an endosomal compartment. For therapeutic application, we have employed high-throughput screening to search for GnT-III inhibitors. These findings highlight the importance of bisecting GlcNAc modification in the nervous system.
Topics: Acetylglucosamine; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Brain; Humans; Models, Biological; Up-Regulation
PubMed: 29909448
DOI: 10.1007/s10719-018-9829-4 -
Journal of Bioenergetics and... Jun 2018The rapidly expanding field of immunometabolism focuses on how metabolism controls the function of immune cells. CD4 T cells are essential for the adaptive immune... (Review)
Review
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. As the rate of O-GlcNAc cycling fluctuates, protein function, stability, and/or localization can be affected. Thus, O-GlcNAc is critically poised at the nexus of cellular metabolism and function. This review highlights the intra- and extracellular metabolic factors that influence CD4 T cell activation and differentiation and how O-GlcNAc regulates these processes. We also propose areas of future research that may illuminate O-GlcNAc's role in the plasticity and pathogenicity of CD4 T cells and uncover new potential therapeutic targets.
Topics: Acetylglucosamine; Animals; CD4-Positive T-Lymphocytes; Humans; Lymphocyte Activation; Protein Processing, Post-Translational
PubMed: 29404877
DOI: 10.1007/s10863-018-9744-1 -
Biochemical Society Transactions Apr 2017Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by... (Review)
Review
Cell division (mitosis) and gamete production (meiosis) are fundamental requirements for normal organismal development. The mammalian cell cycle is tightly regulated by different checkpoints ensuring complete and precise chromosomal segregation and duplication. In recent years, researchers have become increasingly interested in understanding how -GlcNAc regulates the cell cycle. The -GlcNAc post-translation modification is an -glycosidic bond of a single β--acetylglucosamine sugar to serine/threonine residues of intracellular proteins. This modification is sensitive toward changes in nutrient levels in the cellular environment making -GlcNAc a nutrient sensor capable of influencing cell growth and proliferation. Numerous studies have established that O-GlcNAcylation is essential in regulating mitosis and meiosis, while loss of O-GlcNAcylation is lethal in growing cells. Moreover, aberrant O-GlcNAcylation is linked with cancer and chromosomal segregation errors. In this review, we will discuss how -GlcNAc controls different aspects of the cell cycle with a particular emphasis on mitosis and meiosis.
Topics: Acetylglucosamine; Acylation; Animals; Cell Proliferation; Humans; Meiosis; Mitosis; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Proteins
PubMed: 28408472
DOI: 10.1042/BST20160145 -
Cellular Signalling Feb 2022O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA... (Review)
Review
O-GlcNAcylation is a post-translational modification occurring on serine/threonine residues of nuclear and cytoplasmic proteins, mediated by the enzymes OGT and OGA which catalyze the addition or removal of the UDP-GlcNAc moieties, respectively. Structural changes brought by this modification lead to alternations of protein stability, protein-protein interactions, and phosphorylation. Importantly, O-GlcNAcylation is a nutrient sensor by coupling nutrient sensing with cellular signaling. Elevated levels of OGT and O-GlcNAc have been reported in a variety of cancers and has been linked to regulation of multiple cancer signaling pathways. In this review, we discuss the most recent findings on the role of O-GlcNAcylation as a metabolic sensor in signaling pathways and immune response in cancer.
Topics: Acetylglucosamine; Humans; N-Acetylglucosaminyltransferases; Neoplasms; Phosphorylation; Protein Processing, Post-Translational
PubMed: 34800629
DOI: 10.1016/j.cellsig.2021.110201 -
Current Opinion in Structural Biology Jun 2019Extracellular O-GlcNAc is a unique modification restricted to the epidermal growth factor (EGF) domain-containing glycoproteins. This O-GlcNAcylation is catalyzed by the... (Review)
Review
Extracellular O-GlcNAc is a unique modification restricted to the epidermal growth factor (EGF) domain-containing glycoproteins. This O-GlcNAcylation is catalyzed by the EGF-domain specific O-GlcNAc transferase (EOGT), which is localized in the lumen of endoplasmic reticulum. In humans, EOGT is one of the causative genes of a congenital disease, Adams-Oliver syndrome. EOGT is highly expressed in endothelial cells and regulates vascular development and integrity by potentiating Delta-like ligand-mediated Notch signaling. In Drosophila, Eogt modifies Dumpy, an apical extracellular matrix glycoprotein, and affects Dumpy-dependent cell-matrix interaction. In this review, we summarize the current findings of the structure and functions of extracellular O-GlcNAc in animals.
Topics: Acetylglucosamine; Amino Acid Sequence; Animals; Epidermal Growth Factor; Extracellular Space; Humans; Protein Domains
PubMed: 30669087
DOI: 10.1016/j.sbi.2018.12.002 -
Advances in Experimental Medicine and... 2019Chitin is a linear biopolymer composed of β-1,4-linked N-acetylglucosamine (GlcNAc), and an essential component in exoskeleton of insects and crustaceans, the egg...
Chitin is a linear biopolymer composed of β-1,4-linked N-acetylglucosamine (GlcNAc), and an essential component in exoskeleton of insects and crustaceans, the egg shells of parasitic nematodes, and the fungal cell wall. Since the chitin-containing organisms often threaten human health, food safety, and agricultural production, it has been highly desirable to control the hazardous chitin-containing organisms. This book will provide researchers and students with information on the recent research progress about the biology of chitin-containing organisms and their cross-talk with other organisms. This book also contains essential knowledge of drug design for controlling chitin-containing organisms. The authors deeply hope this book brings more attention to the fascinating yet unexploited world of chitin. We would like to thank all contributors for their expertise and generous support.
Topics: Acetylglucosamine; Animals; Cell Wall; Chitin; Crustacea; Fungi; Humans; Insecta; Nematoda
PubMed: 31102239
DOI: 10.1007/978-981-13-7318-3_1 -
Experimental Hematology Sep 2021Posttranslational protein modification through addition of the O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed... (Review)
Review
Posttranslational protein modification through addition of the O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase and O-GlcNAcase, and it acts as a fundamental regulator for a wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics, and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrient availability, and stress. Studies over decades have unveiled the profound biological significance of this unique protein modification in normal physiology and pathologic processes of diverse cell types or tissues. In hematopoiesis, recent studies have indicated the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation, and function of hematopoietic cells including T cells, B cells, myeloid progenitors, and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematologic malignancies with dysregulated epigenetics, metabolism, and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.
Topics: Acetylglucosamine; Animals; Epigenesis, Genetic; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cells; Humans; Protein Processing, Post-Translational
PubMed: 34302904
DOI: 10.1016/j.exphem.2021.07.003 -
Chemical Reviews Feb 2021Protein O-linked β--acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is a unique monosaccharide modification discovered in the early 1980s. With the... (Review)
Review
Protein O-linked β--acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is a unique monosaccharide modification discovered in the early 1980s. With the technological advances in the past several decades, great progress has been made to reveal the biochemistry of O-GlcNAcylation, the substrates of O-GlcNAcylation, and the functional importance of protein O-GlcNAcylation. As a nutrient sensor, protein O-GlcNAcylation plays important roles in almost all biochemical processes examined. Although the functional importance of O-GlcNAcylation of proteins has been extensively reviewed previously, the chemical and biochemical aspects have not been fully addressed. In this review, by critically evaluating key publications in the past 35 years, we aim to provide a comprehensive understanding of this important post-translational modification (PTM) from analytical and biochemical perspectives. Specifically, we will cover (1) multiple analytical advances in the characterization of O-GlcNAc cycling components (i.e., the substrate donor UDP-GlcNAc, the two key enzymes O-GlcNAc transferase and O-GlcNAcase, and O-GlcNAc substrate proteins), (2) the biochemical characterization of the enzymes with a variety of chemical tools, and (3) exploration of O-GlcNAc cycling and its modulating chemicals as potential biomarkers and therapeutic drugs for diseases. Last but not least, we will discuss the challenges and possible solutions for basic and translational research of protein O-GlcNAcylation in the future.
Topics: Acetylglucosamine; Humans; N-Acetylglucosaminyltransferases; beta-N-Acetylhexosaminidases
PubMed: 33416322
DOI: 10.1021/acs.chemrev.0c00884 -
Cancer Letters Apr 2024O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a dynamic post-translational modification (PTM), holds profound implications in controlling various cellular... (Review)
Review
O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a dynamic post-translational modification (PTM), holds profound implications in controlling various cellular processes such as cell signaling, metabolism, and epigenetic regulation that influence cancer progression and therapeutic resistance. From the therapeutic perspective, O-GlcNAc modulates drug efflux, targeting and metabolism. By integrating signals from glucose, lipid, amino acid, and nucleotide metabolic pathways, O-GlcNAc acts as a nutrient sensor and transmits signals to exerts its function on genome stability, epithelial-mesenchymal transition (EMT), cell stemness, cell apoptosis, autophagy, cell cycle. O-GlcNAc also attends to tumor microenvironment (TME) and the immune response. At present, several strategies aiming at targeting O-GlcNAcylation are under mostly preclinical evaluation, where the newly developed O-GlcNAcylation inhibitors markedly enhance therapeutic efficacy. Here we systematically outline the mechanisms through which O-GlcNAcylation influences therapy resistance and deliberate on the prospects and challenges associated with targeting O-GlcNAcylation in future cancer treatments.
Topics: Humans; Sugars; Drug Resistance, Neoplasm; Epigenesis, Genetic; Protein Processing, Post-Translational; Neoplasms; N-Acetylglucosaminyltransferases; Acetylglucosamine; Tumor Microenvironment
PubMed: 38401884
DOI: 10.1016/j.canlet.2024.216742