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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 -
Cancer Letters Jul 2023O-linked β-D-N-acetylglucosamine (O-GlcNAc), as a posttranslational modification (PTM), is a reversible reaction that attaches β-N-GlcNAc to Ser/Thr residues on... (Review)
Review
O-linked β-D-N-acetylglucosamine (O-GlcNAc), as a posttranslational modification (PTM), is a reversible reaction that attaches β-N-GlcNAc to Ser/Thr residues on specific proteins by O-GlcNAc transferase (OGT). O-GlcNAcase (OGA) removes the O-GlcNAc from O-GlcNAcylated proteins. O-GlcNAcylation regulates numerous cellular processes, including signal transduction, the cell cycle, metabolism, and energy homeostasis. Dysregulation of O-GlcNAcylation contributes to the development of various diseases, including cancers. Accumulating evidence has revealed that higher expression levels of OGT and hyper-O-GlcNAcylation are detected in many cancer types and governs glucose metabolism, proliferation, metastasis, invasion, angiogenesis, migration and drug resistance. In this review, we describe the biological functions and molecular mechanisms of OGT- or O-GlcNAcylation-mediated tumorigenesis. Moreover, we discuss the potential role of O-GlcNAcylation in tumor immunotherapy. Furthermore, we highlight that compounds can target O-GlcNAcylation by regulating OGT to suppress oncogenesis. Taken together, targeting protein O-GlcNAcylation might be a promising strategy for the treatment of human malignancies.
Topics: Humans; Protein Processing, Post-Translational; Neoplasms; Proteins; Signal Transduction; Immunotherapy; N-Acetylglucosaminyltransferases; Acetylglucosamine
PubMed: 37279852
DOI: 10.1016/j.canlet.2023.216258 -
Nature Chemistry Jul 2022Liquid-liquid phase separation (LLPS) of SynGAP and PSD-95, two abundant proteins that interact in the postsynaptic density (PSD) of neurons, has been implicated in...
Liquid-liquid phase separation (LLPS) of SynGAP and PSD-95, two abundant proteins that interact in the postsynaptic density (PSD) of neurons, has been implicated in modulating SynGAP PSD enrichment in excitatory synapses. However, the underlying regulatory mechanisms remain enigmatic. Here we report that O-GlcNAcylation of SynGAP acts as a suppressor of LLPS of the SynGAP/PSD-95 complex. We identified multiple O-GlcNAc modification sites for the endogenous SynGAP isolated from rat brain and the recombinantly expressed protein. Protein semisynthesis was used to generate site-specifically O-GlcNAcylated forms of SynGAP, and in vitro and cell-based LLPS assays demonstrated that T1306 O-GlcNAc of SynGAP blocks the interaction with PSD-95, thus inhibiting LLPS. Furthermore, O-GlcNAcylation suppresses SynGAP/PSD-95 LLPS in a dominant-negative manner, enabling sub-stoichiometric O-GlcNAcylation to exert effective regulation. We also showed that O-GlcNAc-dependent LLPS is reversibly regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). These findings demonstrate that OGT- and OGA-catalysed O-GlcNAc cycling may serve as an LLPS-regulating post-translational modification.
Topics: Acetylglucosamine; Animals; Neurons; Protein Processing, Post-Translational; Rats
PubMed: 35637289
DOI: 10.1038/s41557-022-00946-9 -
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 -
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 -
Clinical Science (London, England :... Nov 2023O-Linked attachment of β-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and... (Review)
Review
O-Linked attachment of β-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear, cytoplasmic, and mitochondrial proteins is a highly dynamic and ubiquitous post-translational modification that impacts the function, activity, subcellular localization, and stability of target proteins. Physiologically, acute O-GlcNAcylation serves primarily to modulate cellular signaling and transcription regulatory pathways in response to nutrients and stress. To date, thousands of proteins have been revealed to be O-GlcNAcylated and this number continues to grow as the technology for the detection of O-GlcNAc improves. The attachment of a single O-GlcNAc is catalyzed by the enzyme O-GlcNAc transferase (OGT), and their removal is catalyzed by O-GlcNAcase (OGA). O-GlcNAcylation is regulated by the metabolism of glucose via the hexosamine biosynthesis pathway, and the metabolic abnormalities associated with pathophysiological conditions are all associated with increased flux through this pathway and elevate O-GlcNAc levels. While chronic O-GlcNAcylation is well associated with cardiovascular dysfunction, only until recently, and with genetically modified animals, has O-GlcNAcylation as a contributing mechanism of cardiovascular disease emerged. This review will address and critically evaluate the current literature on the role of O-GlcNAcylation in vascular physiology, with a view that this pathway can offer novel targets for the treatment and prevention of cardiovascular diseases.
Topics: Animals; Protein Processing, Post-Translational; Acetylglucosaminidase; Phosphorylation; Nutrients; N-Acetylglucosaminyltransferases; Acetylglucosamine
PubMed: 37986614
DOI: 10.1042/CS20220309 -
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 -
The Journal of Biological Chemistry Nov 2023Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies.... (Review)
Review
Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-specific pathways that contribute to cancer cell survival, proliferation, and progression. A special type of glycosylation that has been gaining momentum in cancer research is the modification of nuclear, cytoplasmic, and mitochondrial proteins, termed O-GlcNAcylation. This protein modification is catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses the final product of the Hexosamine Biosynthetic Pathway (HBP) to connect altered nutrient availability to changes in cellular signaling that contribute to multiple aspects of tumor progression. Both O-GlcNAc and its enzyme OGT are highly elevated in cancer and fulfill the crucial role in regulating many hallmarks of cancer. In this review, we present and discuss the latest findings elucidating the involvement of OGT and O-GlcNAc in cancer.
Topics: Humans; Acetylglucosamine; Biosynthetic Pathways; Glycosylation; N-Acetylglucosaminyltransferases; Neoplasms; Protein Processing, Post-Translational
PubMed: 37838167
DOI: 10.1016/j.jbc.2023.105344