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Nature Reviews. Rheumatology Jan 2023Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal... (Review)
Review
Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal transduction. In many rheumatic diseases, a shift in protein glycosylation occurs, and is associated with inflammatory processes and disease progression. For example, the Fc-glycan composition on (auto)antibodies is associated with disease activity, and the presence of additional glycans in the antigen-binding domains of some autoreactive B cell receptors can affect B cell activation. In addition, changes in synovial fibroblast cell-surface glycosylation can alter the synovial microenvironment and are associated with an altered inflammatory state and disease activity in rheumatoid arthritis. The development of our understanding of the role of glycosylation of plasma proteins (particularly (auto)antibodies), cells and tissues in rheumatic pathological conditions suggests that glycosylation-based interventions could be used in the treatment of these diseases.
Topics: Humans; Glycomics; Glycosylation; Rheumatic Diseases; Arthritis, Rheumatoid
PubMed: 36418483
DOI: 10.1038/s41584-022-00867-4 -
Annual Review of Pathology 2015Neoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic... (Review)
Review
Neoplastic transformation results in a wide variety of cellular alterations that impact the growth, survival, and general behavior of affected tissue. Although genetic alterations underpin the development of neoplastic disease, epigenetic changes can exert an equally significant effect on neoplastic transformation. Among neoplasia-associated epigenetic alterations, changes in cellular glycosylation have recently received attention as a key component of neoplastic progression. Alterations in glycosylation appear to not only directly impact cell growth and survival but also facilitate tumor-induced immunomodulation and eventual metastasis. Many of these changes may support neoplastic progression, and unique alterations in tumor-associated glycosylation may also serve as a distinct feature of cancer cells and therefore provide novel diagnostic and even therapeutic targets.
Topics: Animals; Cell Transformation, Neoplastic; Epigenesis, Genetic; Glycosylation; Humans; Neoplasm Proteins; Neoplasms
PubMed: 25621663
DOI: 10.1146/annurev-pathol-012414-040438 -
Genes Apr 2023The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate--acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for - or -linked... (Review)
Review
The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate--acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for - or -linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and -acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for -glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how -GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein -glycosylation and -GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.
Topics: Hexosamines; Protein Processing, Post-Translational; Glucosamine; Glycosylation; TOR Serine-Threonine Kinases
PubMed: 37107691
DOI: 10.3390/genes14040933 -
Current Biology : CB Apr 2019Eichler introduces the diversity of protein glycosylations and the roles of these modifications in regulating protein function.
Eichler introduces the diversity of protein glycosylations and the roles of these modifications in regulating protein function.
Topics: Glycosylation; Proteins
PubMed: 30939300
DOI: 10.1016/j.cub.2019.01.003 -
Advances in understanding N-glycosylation structure, function, and regulation in health and disease.European Journal of Cell Biology 2021N-linked glycosylation is a post-translational modification crucial for membrane protein folding, stability and other cellular functions. Alteration of membrane protein... (Review)
Review
N-linked glycosylation is a post-translational modification crucial for membrane protein folding, stability and other cellular functions. Alteration of membrane protein N-glycans is implicated in wide range of pathological conditions including cancer metastasis, chronic inflammatory diseases, and viral pathogenesis. Even though the roles of N-glycans have been studied extensively, our knowledge of their mechanisms remains unclear due to the lack of detailed structural analysis of the N-glycome. Mapping the N-glycome landscape will open new avenues to explore disease mechanisms and identify novel therapeutic targets. This review discusses the diverse structure of N-linked glycans, the function and regulation of N-glycosylation in health and disease, and ends with a focus on recent approaches to target N-glycans in rheumatoid arthritis and cancer metastasis.
Topics: Glycosylation; Polysaccharides; Protein Processing, Post-Translational
PubMed: 34839178
DOI: 10.1016/j.ejcb.2021.151186 -
Cell Death and Differentiation Aug 2023Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal malignancy partially due to the acquired alterations related to aberrant protein glycosylation that...
Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal malignancy partially due to the acquired alterations related to aberrant protein glycosylation that pathologically remodel molecular biological processes and protect PDAC cells from death. Ferroptosis driven by lethal lipid peroxidation provides a targetable vulnerability for PDAC. However, the crosstalk between glycosylation and ferroptosis remains unclear. Here, we identified 4F2hc, a subunit of the glutamate-cystine antiporter system X, and its asparagine (N)-glycosylation is involved in PDAC ferroptosis by N- and O-linked glycoproteomics. Knockdown of SLC3A2 (gene name of 4F2hc) or blocking the N-glycosylation of 4F2hc potentiates ferroptosis sensitization of PDAC cells by impairing the activity of system X manifested by a marked decrease in intracellular glutathione. Mechanistically, we found that the glycosyltransferase B3GNT3 catalyzes the glycosylation of 4F2hc, stabilizes the 4F2hc protein, and enhances the interaction between 4F2hc and xCT. Knockout of B3GNT3 or deletion of enzymatically active B3GNT3 sensitizes PDAC cells to ferroptosis. Reconstitution of 4F2hc-deficient cells with wildtype 4F2hc restores ferroptosis resistance while glycosylation-mutated 4F2hc does not. Additionally, upon combination with a ferroptosis inducer, treatment with the classical N-glycosylation inhibitor tunicamycin (TM) markedly triggers the overactivation of lipid peroxidation and enhances the sensitivity of PDAC cells to ferroptosis. Notably, we confirmed that genetic perturbation of SLC3A2 or combination treatment with TM significantly augments ferroptosis-induced inhibition of orthotopic PDAC. Clinically, high expression of 4F2hc and B3GNT3 contributes to the progression and poor survival of PDAC patients. Collectively, our findings reveal a previously unappreciated function of N-glycosylation of 4F2hc in ferroptosis and suggest that dual targeting the vulnerabilities of N-glycosylation and ferroptosis may be an innovative therapeutic strategy for PDAC.
Topics: Humans; Glycosylation; Ferroptosis; Glycosyltransferases; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; N-Acetylglucosaminyltransferases
PubMed: 37479744
DOI: 10.1038/s41418-023-01188-z -
Theranostics 2023Cell surface glycosylation has a variety of functions, and its dysregulation in cancer contributes to impaired signaling, metastasis and the evasion of the immune... (Review)
Review
Cell surface glycosylation has a variety of functions, and its dysregulation in cancer contributes to impaired signaling, metastasis and the evasion of the immune responses. Recently, a number of glycosyltransferases that lead to altered glycosylation have been linked to reduced anti-tumor immune responses: B3GNT3, which is implicated in PD-L1 glycosylation in triple negative breast cancer, FUT8, through fucosylation of B7H3, and B3GNT2, which confers cancer resistance to T cell cytotoxicity. Given the increased appreciation of the relevance of protein glycosylation, there is a critical need for the development of methods that allow for an unbiased interrogation of cell surface glycosylation status. Here we provide an overview of the broad changes in glycosylation at the surface of cancer cell and describe selected examples of receptors with aberrant glycosylation leading to functional changes, with emphasis on immune checkpoint inhibitors, growth-promoting and growth-arresting receptors. Finally, we posit that the field of glycoproteomics has matured to an extent where large-scale profiling of intact glycopeptides from the cell surface is feasible and is poised for discovery of new actionable targets against cancer.
Topics: Humans; Glycosylation; Cell Membrane; Glycopeptides; Triple Negative Breast Neoplasms; Carrier Proteins
PubMed: 37215580
DOI: 10.7150/thno.81760 -
Current Opinion in Structural Biology Dec 2022
Topics: Glycosylation; Carbohydrates
PubMed: 36179500
DOI: 10.1016/j.sbi.2022.102468 -
Chemical Reviews Dec 2016Chemical tools have accelerated progress in glycoscience, reducing experimental barriers to studying protein glycosylation, the most widespread and complex form of... (Review)
Review
Chemical tools have accelerated progress in glycoscience, reducing experimental barriers to studying protein glycosylation, the most widespread and complex form of posttranslational modification. For example, chemical glycoproteomics technologies have enabled the identification of specific glycosylation sites and glycan structures that modulate protein function in a number of biological processes. This field is now entering a stage of logarithmic growth, during which chemical innovations combined with mass spectrometry advances could make it possible to fully characterize the human glycoproteome. In this review, we describe the important role that chemical glycoproteomics methods are playing in such efforts. We summarize developments in four key areas: enrichment of glycoproteins and glycopeptides from complex mixtures, emphasizing methods that exploit unique chemical properties of glycans or introduce unnatural functional groups through metabolic labeling and chemoenzymatic tagging; identification of sites of protein glycosylation; targeted glycoproteomics; and functional glycoproteomics, with a focus on probing interactions between glycoproteins and glycan-binding proteins. Our goal with this survey is to provide a foundation on which continued technological advancements can be made to promote further explorations of protein glycosylation.
Topics: Carbohydrates; Glycoproteins; Glycosylation; Humans; Jurkat Cells; Mass Spectrometry; Oxidation-Reduction; Proteomics
PubMed: 27960262
DOI: 10.1021/acs.chemrev.6b00023 -
Current Opinion in Structural Biology Aug 2022The structure and post-translational processing of the SARS-CoV-2 spike glycoprotein (S) is intimately associated with the function of the virus and of sterilising... (Review)
Review
The structure and post-translational processing of the SARS-CoV-2 spike glycoprotein (S) is intimately associated with the function of the virus and of sterilising vaccines. The surface of the S protein is extensively modified by glycans, and their biosynthesis is driven by both the wider cellular context, and importantly, the underlining protein structure and local glycan density. Comparison of virally derived S protein with both recombinantly derived and adenovirally induced proteins, reveal hotspots of protein-directed glycosylation that drive conserved glycosylation motifs. Molecular dynamics simulations revealed that, while the S surface is extensively shielded by N-glycans, it presents regions vulnerable to neutralising antibodies. Furthermore, glycans have been shown to influence the accessibility of the receptor binding domain and the binding to the cellular receptor. The emerging picture is one of unifying, principles of S protein glycosylation and an intimate role of glycosylation in immunogen structure and efficacy.
Topics: COVID-19; Glycosylation; Humans; Polysaccharides; Protein Binding; SARS-CoV-2
PubMed: 35717706
DOI: 10.1016/j.sbi.2022.102402