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Cells Nov 2022The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational... (Review)
Review
The modification of nuclear, mitochondrial, and cytosolic proteins by O-linked βN-acetylglucosamine (O-GlcNAc) has emerged as a dynamic and essential post-translational modification of mammalian proteins. O-GlcNAc is cycled on and off over 5000 proteins in response to diverse stimuli impacting protein function and, in turn, epigenetics and transcription, translation and proteostasis, metabolism, cell structure, and signal transduction. Environmental and physiological injury lead to complex changes in O-GlcNAcylation that impact cell and tissue survival in models of heat shock, osmotic stress, oxidative stress, and hypoxia/reoxygenation injury, as well as ischemic reperfusion injury. Numerous mechanisms that appear to underpin O-GlcNAc-mediated survival include changes in chaperone levels, impacts on the unfolded protein response and integrated stress response, improvements in mitochondrial function, and reduced protein aggregation. Here, we discuss the points at which O-GlcNAc is integrated into the cellular stress response, focusing on the roles it plays in the cardiovascular system and in neurodegeneration.
Topics: Animals; Acetylglucosamine; Protein Processing, Post-Translational; Glycosylation; Oxidative Stress; Signal Transduction; Proteins; Mammals
PubMed: 36359905
DOI: 10.3390/cells11213509 -
Orphanet Journal of Rare Diseases Dec 2016Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the... (Review)
Review
Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the Finnish population. It is a lifelong condition affecting on the patient's appearance, cognition, adaptive skills, physical growth, personality, body structure, and health. An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU. Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50 years.The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA), which leads to a disorder in the degradation of glycoasparagines - aspartylglucosamine or other glycoconjugates with an aspartylglucosamine moiety at their reducing end - and accumulation of these undegraded glycoasparagines in tissues and body fluids. A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population. Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population. A mouse strain, which completely lacks the Aga activity has been generated through targeted disruption of the Aga gene in embryonic stem cells. These Aga-deficient mice share most of the clinical, histopathologic and biochemical characteristics of human AGU disease. Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals. The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol. Enzyme replacement trials on human AGU patients have not been reported so far. Allogenic stem cell transplantation has not proved effective in curing AGU.
Topics: Acetylglucosamine; Animals; Aspartylglucosaminuria; Aspartylglucosylaminase; Glycoproteins; Humans; Lysosomal Storage Diseases; Mutation
PubMed: 27906067
DOI: 10.1186/s13023-016-0544-6 -
Biochimica Et Biophysica Acta. Reviews... Nov 2022O-GlcNAcylation is a posttranslational modification that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine and threonine residues of proteins. Such a... (Review)
Review
O-GlcNAcylation is a posttranslational modification that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to the serine and threonine residues of proteins. Such a glycosylation would alter the activities, stabilities, and interactions of target proteins that are functional in a wide range of biological processes and diseases. Accumulating evidence indicates that O-GlcNAcylation is tightly associated with hepatocellular carcinoma (HCC) in its onset, growth, invasion and metastasis, drug resistance, and stemness. Here we summarize the discoveries of the role of O-GlcNAcylation in HCC and its function mechanism, aiming to deepen our understanding of HCC pathology, generate more biomarkers for its diagnosis and prognosis, and offer novel molecular targets for its treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Acetylglucosamine; Protein Processing, Post-Translational; Glycosylation
PubMed: 36152903
DOI: 10.1016/j.bbcan.2022.188806 -
Pathology, Research and Practice Jan 2024One of the general characteristics of cancer cells is the abnormal increase of O-GlcNAcylation. Recent studies have shown that it affects the basic functions of proteins... (Review)
Review
One of the general characteristics of cancer cells is the abnormal increase of O-GlcNAcylation. Recent studies have shown that it affects the basic functions of proteins and regulates multiple phenotypes of cancer cells through key signals and metabolic pathways. O-GlcNAcylation is a covalent linkage between the β-D-N-acetylglucosamine (GlcNAc) sugar and target protein. It interacts with many other types of post-translational modifications and works together in the whole process of cancer development. For example, it regulates cell activities such as cell signal transduction, transcription, cell division, metabolism and cytoskeleton regulation. In this review, we summarized the general concept of O-GlcNAcylation and its related role in the ten major tumor phenotypes.
Topics: Humans; Neoplasms; Protein Processing, Post-Translational; Proteins; Biology; Acetylglucosamine; N-Acetylglucosaminyltransferases
PubMed: 38043191
DOI: 10.1016/j.prp.2023.155001 -
Current Opinion in Structural Biology Jun 2019Glycosylation, or the addition of sugars to proteins, is a highly conserved protein modification defined by both the monosaccharide initially added as well as the amino... (Review)
Review
Glycosylation, or the addition of sugars to proteins, is a highly conserved protein modification defined by both the monosaccharide initially added as well as the amino acid to which it is attached. O-Linked glycosylation represents a diverse group of protein modifications occurring on the hydroxyl groups of serine and/or threonine residues. O-Glycosylation can have wide-ranging effects on protein stability and function, which translate into crucial consequences at the organismal level. This review will summarize structural and biological insights into the major O-glycans formed within the secretory apparatus (O-GalNAc, O-Man, O-Fuc, O-Glc and extracellular O-GlcNAc) from studies in the fruit fly Drosophila melanogaster. Drosophila has many advantages for investigating these complex modifications, boasting reduced functional redundancy within gene families, reduced length/complexity of glycan chains and sophisticated genetic tools. Gaining an understanding of the normal cellular and developmental roles of these conserved modifications in Drosophila will provide insight into how changes in O-glycans are involved in human disease and disease susceptibilities.
Topics: Acetylglucosamine; Animals; Drosophila melanogaster; Extracellular Space; Glycosylation; Humans; Oxygen
PubMed: 30852302
DOI: 10.1016/j.sbi.2019.01.014 -
Biochemical Society Transactions Apr 2017The post-translational modification of serine and threonine residues of proteins found in numerous subcellular locations by -linked -acetylglucosamine (-GlcNAc) is... (Review)
Review
The post-translational modification of serine and threonine residues of proteins found in numerous subcellular locations by -linked -acetylglucosamine (-GlcNAc) is emerging as a key mediator of many cardiovascular pathophysiological processes. Early studies implicated increased protein O-GlcNAcylation as contributing to the cardiovascular complications associated with diabetes, whereas subsequent studies demonstrated that acute increases in -GlcNAc levels were protective against ischemia/reperfusion injury. There is now a growing understanding that -GlcNAc modification of proteins influences numerous cellular functions, including transcription, protein turnover, calcium handling, and bioenergetics. As a result, a more nuanced view of the role of protein O-GlcNAcylation in the cardiovascular system is emerging along with the recognition that it is required for normal cellular function and homeostasis. Consequently, the impact of changes in -GlcNAc cycling due to stress or disease on the heart is complex and highly dependent on the specific context of these events. The goal of this review is to provide an overview of some of the more recent advances in our understanding of the role O-GlcNAcylation plays in mediating cardiovascular function and disease.
Topics: Acetylglucosamine; Animals; Cardiovascular Diseases; Diabetes Mellitus; Gene Expression Regulation; Glycosylation; Humans; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 28408494
DOI: 10.1042/BST20160164 -
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 -
Nature Communications Oct 2023O-GlcNAcylation is a conserved post-translational modification that attaches N-acetyl glucosamine (GlcNAc) to myriad cellular proteins. In response to nutritional and...
O-GlcNAcylation is a conserved post-translational modification that attaches N-acetyl glucosamine (GlcNAc) to myriad cellular proteins. In response to nutritional and hormonal signals, O-GlcNAcylation regulates diverse cellular processes by modulating the stability, structure, and function of target proteins. Dysregulation of O-GlcNAcylation has been implicated in the pathogenesis of cancer, diabetes, and neurodegeneration. A single pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), catalyzes the addition and removal of O-GlcNAc on over 3,000 proteins in the human proteome. However, how OGT selects its native substrates and maintains the homeostatic control of O-GlcNAcylation of so many substrates against OGA is not fully understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of human OGT and the OGT-OGA complex. Our studies reveal that OGT forms a functionally important scissor-shaped dimer. Within the OGT-OGA complex structure, a long flexible OGA segment occupies the extended substrate-binding groove of OGT and positions a serine for O-GlcNAcylation, thus preventing OGT from modifying other substrates. Conversely, OGT disrupts the functional dimerization of OGA and occludes its active site, resulting in the blocking of access by other substrates. This mutual inhibition between OGT and OGA may limit the futile O-GlcNAcylation cycles and help to maintain O-GlcNAc homeostasis.
Topics: Humans; Acetylglucosamine; Acetylglucosaminidase; Cryoelectron Microscopy; N-Acetylglucosaminyltransferases; Protein Processing, Post-Translational; Proteins
PubMed: 37907462
DOI: 10.1038/s41467-023-42427-8 -
Glycobiology Nov 2018O-GlcNAcylation, analogous to phosphorylation, is an essential post-translational modification of proteins at Ser/Thr residues with a single β-N-acetylglucosamine... (Review)
Review
O-GlcNAcylation, analogous to phosphorylation, is an essential post-translational modification of proteins at Ser/Thr residues with a single β-N-acetylglucosamine moiety. This dynamic protein modification regulates many fundamental cellular processes and its deregulation has been linked to chronic diseases such as cancer, diabetes and neurodegenerative disorders. Reversible attachment and removal of O-GlcNAc is governed only by O-GlcNAc transferase and O-GlcNAcase, respectively. Peptide substrates, derived from natural O-GlcNAcylation targets, function in the catalytic cores of these two enzymes by maintaining interactions between enzyme and substrate, which makes them ideal models for the study of O-GlcNAcylation and deglycosylation. These peptides provide valuable tools for a deeper understanding of O-GlcNAc processing enzymes. By taking advantage of peptide chemistry, recent progress in the study of activity and regulatory mechanisms of these two enzymes has advanced our understanding of their fundamental specificities as well as their potential as therapeutic targets. Hence, this review summarizes the recent achievements on this modification studied at the peptide level, focusing on enzyme activity, enzyme specificity, direct function, site-specific antibodies and peptide substrate-inspired inhibitors.
Topics: Acetylglucosamine; Animals; Humans; N-Acetylglucosaminyltransferases; Substrate Specificity; beta-N-Acetylhexosaminidases
PubMed: 29635275
DOI: 10.1093/glycob/cwy031 -
Journal of Alzheimer's Disease : JAD 2024As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems,... (Review)
Review
As a non-classical post-translational modification, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) is widely found in human organ systems, particularly in our brains, and is indispensable for healthy cell biology. With the increasing age of the global population, the incidence of neurodegenerative diseases is increasing, too. The common characteristic of these disorders is the aggregation of abnormal proteins in the brain. Current research has found that O-GlcNAcylation dysregulation is involved in misfolding or aggregation of these abnormal proteins to mediate disease progression, but the specific mechanism has not been defined. This paper reviews recent studies on O-GlcNAcylation's roles in several neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, Machado-Joseph's disease, and giant axonal neuropathy, and shows that O-GlcNAcylation, as glucose metabolism sensor, mediating synaptic function, participating in oxidative stress response and signaling pathway conduction, directly or indirectly regulates characteristic pathological protein toxicity and affects disease progression. The existing results suggest that targeting O-GlcNAcylation will provide new ideas for clinical diagnosis, prevention, and treatment of neurodegenerative diseases.
Topics: Humans; Neurodegenerative Diseases; Protein Processing, Post-Translational; Proteins; Alzheimer Disease; Acetylglucosamine; Disease Progression; N-Acetylglucosaminyltransferases
PubMed: 38250776
DOI: 10.3233/JAD-230955