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Nature Reviews. Molecular Cell Biology Jul 2017O-GlcNAcylation - the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins - is a post-translational... (Review)
Review
O-GlcNAcylation - the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins - is a post-translational modification that regulates fundamental cellular processes in metazoans. A single pair of enzymes - O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) - controls the dynamic cycling of this protein modification in a nutrient- and stress-responsive manner. Recent years have seen remarkable advances in our understanding of O-GlcNAcylation at levels that range from structural and molecular biology to cell signalling and gene regulation to physiology and disease. New mechanisms and functions of O-GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.
Topics: Acetylglucosamine; Animals; Humans; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 28488703
DOI: 10.1038/nrm.2017.22 -
Physiological Reviews Apr 2021In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a -acetylglucosamine moiety (-GlcNAc) via an... (Review)
Review
In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a -acetylglucosamine moiety (-GlcNAc) via an -linkage overturned the widely held assumption that glycosylation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to traditional glycosylation, the -GlcNAc modification does not lead to complex, branched glycan structures and is rapidly cycled on and off proteins by -GlcNAc transferase (OGT) and -GlcNAcase (OGA), respectively. Since its discovery, -GlcNAcylation has been shown to contribute to numerous cellular functions, including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in -GlcNAc cycling has been implicated in the progression of a wide range of diseases, such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current understanding of the processes involved in regulating -GlcNAc turnover, the role of -GlcNAcylation in regulating cellular physiology, and how dysregulation in -GlcNAc cycling contributes to pathophysiological processes.
Topics: Acetylglucosamine; Animals; Cell Physiological Phenomena; Glycosylation; Humans; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational
PubMed: 32730113
DOI: 10.1152/physrev.00043.2019 -
The Journal of Clinical Investigation Apr 2023Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of...
Major depressive disorder is a common and devastating psychiatric disease, and the prevalence and burden are substantially increasing worldwide. Multiple studies of depression patients have implicated glucose metabolic dysfunction in the pathophysiology of depression. However, the molecular mechanisms by which glucose and related metabolic pathways modulate depressive-like behaviors are largely uncharacterized. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is a glucose metabolite with pivotal functions as a donor molecule for O-GlcNAcylation. O-GlcNAc transferase (OGT), a key enzyme in protein O-GlcNAcylation, catalyzes protein posttranslational modification by O-GlcNAc and acts as a stress sensor. Here, we show that Ogt mRNA was increased in depression patients and that astroglial OGT expression was specifically upregulated in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social-defeat stress. The selective deletion of astrocytic OGT resulted in antidepressant-like effects, and moreover, astrocytic OGT in the mPFC bidirectionally regulated vulnerability to social stress. Furthermore, OGT modulated glutamatergic synaptic transmission through O-GlcNAcylation of glutamate transporter-1 (GLT-1) in astrocytes. OGT astrocyte-specific knockout preserved the neuronal morphology atrophy and Ca2+ activity deficits caused by chronic stress and resulted in antidepressant effects. Our study reveals that astrocytic OGT in the mPFC regulates depressive-like behaviors through the O-GlcNAcylation of GLT-1 and could be a potential target for antidepressants.
Topics: Mice; Animals; Astrocytes; Depressive Disorder, Major; Depression; Synaptic Transmission; N-Acetylglucosaminyltransferases; Antidepressive Agents; Glucose; Acetylglucosamine
PubMed: 36757814
DOI: 10.1172/JCI160016 -
Cell Jan 2023O-GlcNAc is a dynamic post-translational modification (PTM) that regulates protein functions. In studying the regulatory roles of O-GlcNAc, a major roadblock is the...
O-GlcNAc is a dynamic post-translational modification (PTM) that regulates protein functions. In studying the regulatory roles of O-GlcNAc, a major roadblock is the inability to change O-GlcNAcylation on a single protein at a time. Herein, we developed a dual RNA-aptamer-based approach that simultaneously targeted O-GlcNAc transferase (OGT) and β-catenin, the key transcription factor of the Wnt signaling pathway, to selectively increase O-GlcNAcylation of the latter without affecting other OGT substrates. Using the OGT/β-catenin dual-specificity aptamers, we found that O-GlcNAcylation of β-catenin stabilizes the protein by inhibiting its interaction with β-TrCP. O-GlcNAc also increases β-catenin's interaction with EZH2, recruits EZH2 to promoters, and dramatically alters the transcriptome. Further, by coupling riboswitches or an inducible expression system to aptamers, we enabled inducible regulation of protein-specific O-GlcNAcylation. Together, our findings demonstrate the efficacy and versatility of dual-specificity aptamers for regulating O-GlcNAcylation on individual proteins.
Topics: Aptamers, Nucleotide; beta Catenin; Protein Processing, Post-Translational; Wnt Signaling Pathway; N-Acetylglucosaminyltransferases; Acetylglucosamine
PubMed: 36626902
DOI: 10.1016/j.cell.2022.12.016 -
Molecules (Basel, Switzerland) Feb 2023Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for... (Review)
Review
Microbial production of hyaluronic acid (HA) is an area of research that has been gaining attention in recent years due to the increasing demand for this biopolymer for several industrial applications. Hyaluronic acid is a linear, non-sulfated glycosaminoglycan that is widely distributed in nature and is mainly composed of repeating units of N-acetylglucosamine and glucuronic acid. It has a wide and unique range of properties such as viscoelasticity, lubrication, and hydration, which makes it an attractive material for several industrial applications such as cosmetics, pharmaceuticals, and medical devices. This review presents and discusses the available fermentation strategies to produce hyaluronic acid.
Topics: Hyaluronic Acid; Fermentation; Chemical Phenomena; Acetylglucosamine; Glucuronic Acid
PubMed: 36903332
DOI: 10.3390/molecules28052084 -
International Journal of Molecular... Sep 2022Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure... (Review)
Review
Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field.
Topics: Acetylglucosamine; Hexosamines; Homeostasis; Kidney; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational
PubMed: 36232558
DOI: 10.3390/ijms231911260 -
Journal of Neuroinflammation Sep 2023In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite...
BACKGROUND
In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence.
OBJECTIVES AND METHODS
An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS).
RESULTS
Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces T1, T17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points.
CONCLUSIONS
Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.
Topics: Humans; Animals; Mice; Acetylglucosamine; Interleukin-17; Glatiramer Acetate; Interleukin-6; Multiple Sclerosis; Inflammation; Encephalitis; Cytokines
PubMed: 37705084
DOI: 10.1186/s12974-023-02893-9 -
Frontiers in Endocrinology 2020The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be... (Review)
Review
The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be fine-tuned in space and time. A multitude of post-translational modifications (PTMs) have been implicated in centrosome modulation, including phosphorylation, ubiquitination and acetylation. Among them is the emerging O-linked N-acetylglucosamine (O-GlcNAc) modification. This quintessential PTM has a sole writer, O-GlcNAc transferase (OGT), and the only eraser, O-GlcNAcase (OGA). O-GlcNAc couples glucose metabolism with signal transduction and forms a yin-yang relationship with phosphorylation. Evidence from proteomic studies as well as single protein investigations has pinpointed a role of O-GlcNAc in centrosome number and separation, centriole number and distribution, as well as the cilia machinery emanating from the centrosomes. Herein we review our current understanding of the sweet modification embedded in centrosome dynamics and speculate that more molecular details will be unveiled in the future.
Topics: Acetylglucosamine; Animals; Centrosome; Cilia; Humans; N-Acetylglucosaminyltransferases
PubMed: 33597927
DOI: 10.3389/fendo.2020.621888 -
Experimental & Molecular Medicine Nov 2021O-GlcNAcylation is a posttranslational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of many proteins. This protein... (Review)
Review
O-GlcNAcylation is a posttranslational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to serine or threonine residues of many proteins. This protein modification interacts with key cellular pathways involved in transcription, translation, and proteostasis. Although ubiquitous throughout the body, O-GlcNAc is particularly abundant in the brain, and various proteins commonly found at synapses are O-GlcNAcylated. Recent studies have demonstrated that the modulation of O-GlcNAc in the brain alters synaptic and neuronal functions. Furthermore, altered brain O-GlcNAcylation is associated with either the etiology or pathology of numerous neurodegenerative diseases, while the manipulation of O-GlcNAc exerts neuroprotective effects against these diseases. Although the detailed molecular mechanisms underlying the functional roles of O-GlcNAcylation in the brain remain unclear, O-GlcNAcylation is critical for regulating diverse neural functions, and its levels change during normal and pathological aging. In this review, we will highlight the functional importance of O-GlcNAcylation in the brain and neurodegenerative diseases.
Topics: Acetylglucosamine; Aging; Animals; Biomarkers; Brain; Diagnosis, Differential; Disease Susceptibility; Gene Expression Regulation; Glycosylation; Homeostasis; Humans; Neurodegenerative Diseases; Neurons; Protein Processing, Post-Translational
PubMed: 34837015
DOI: 10.1038/s12276-021-00709-5 -
Molecular Metabolism Sep 2023O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein...
OBJECTIVE
O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD.
METHODS
We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD.
RESULTS
O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD.
CONCLUSIONS
These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.
Topics: Humans; Mice; Animals; Non-alcoholic Fatty Liver Disease; Down-Regulation; Acetylglucosamine; Mitochondria; Hepatocytes; Lipids
PubMed: 37453647
DOI: 10.1016/j.molmet.2023.101776