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Nature Reviews. Molecular Cell Biology Jun 2012Protein glycosylation is a ubiquitous post-translational modification found in all domains of life. Despite their significant complexity in animal systems, glycan... (Review)
Review
Protein glycosylation is a ubiquitous post-translational modification found in all domains of life. Despite their significant complexity in animal systems, glycan structures have crucial biological and physiological roles, from contributions in protein folding and quality control to involvement in a large number of biological recognition events. As a result, they impart an additional level of 'information content' to underlying polypeptide structures. Improvements in analytical methodologies for dissecting glycan structural diversity, along with recent developments in biochemical and genetic approaches for studying glycan biosynthesis and catabolism, have provided a greater understanding of the biological contributions of these complex structures in vertebrates.
Topics: Animals; Cell Membrane; Cytosol; Endoplasmic Reticulum; Glycoproteins; Glycosylation; Golgi Apparatus; Humans; Metabolism; Models, Biological; Polysaccharides; Protein Conformation; Protein Denaturation; Protein Folding; Protein Processing, Post-Translational; Proteins
PubMed: 22722607
DOI: 10.1038/nrm3383 -
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 -
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 -
Current Opinion in Structural Biology Dec 2022
Topics: Glycosylation; Carbohydrates
PubMed: 36179500
DOI: 10.1016/j.sbi.2022.102468 -
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 -
Biotechnology Advances Sep 2023Glycosylation-mediated post-translational modification is critical for regulating many fundamental processes like cell division, differentiation, immune response, and... (Review)
Review
Glycosylation-mediated post-translational modification is critical for regulating many fundamental processes like cell division, differentiation, immune response, and cell-to-cell interaction. Alterations in the N-linked or O-linked glycosylation pattern of regulatory proteins like transcription factors or cellular receptors lead to many diseases, including cancer. These alterations give rise to micro- and macro-heterogeneity in tumor cells. Here, we review the role of O- and N-linked glycosylation and its regulatory function in autoimmunity and aberrant glycosylation in cancer. The change in cellular glycome could result from a change in the expression of glycosidases or glycosyltransferases like N-acetyl-glucosaminyl transferase V, FUT8, ST6Gal-I, DPAGT1, etc., impact the glycosylation of target proteins leading to transformation. Moreover, the mutations in glycogenes affect glycosylation patterns on immune cells leading to other related manifestations like pro- or anti-inflammatory effects. In recent years, understanding the glycome to cancer indicates that it can be utilized for both diagnosis/prognosis as well as immunotherapy. Studies involving mass spectrometry of proteome, site- and structure-specific glycoproteomics, or transcriptomics/genomics of patient samples and cancer models revealed the importance of glycosylation homeostasis in cancer biology. The development of emerging technologies, such as the lectin microarray, has facilitated research on the structure and function of glycans and glycosylation. Newly developed devices allow for high-throughput, high-speed, and precise research on aberrant glycosylation. This paper also discusses emerging technologies and clinical applications of glycosylation.
Topics: Humans; Glycosylation; Neoplasms; Glycosyltransferases; Lectins; Immunotherapy; Polysaccharides
PubMed: 37030554
DOI: 10.1016/j.biotechadv.2023.108149 -
Ageing Research Reviews Aug 2023Glycosylation is a common post-translational modification of brain proteins including cell surface adhesion molecules, synaptic proteins, receptors and channels, as well... (Review)
Review
Glycosylation is a common post-translational modification of brain proteins including cell surface adhesion molecules, synaptic proteins, receptors and channels, as well as intracellular proteins, with implications in brain development and functions. Using advanced state-of-the-art glycomics and glycoproteomics technologies in conjunction with glycoinformatics resources, characteristic glycosylation profiles in brain tissues are increasingly reported in the literature and growing evidence shows deregulation of glycosylation in central nervous system disorders, including aging associated neurodegenerative diseases. Glycan signatures characteristic of brain tissue are also frequently described in cerebrospinal fluid due to its enrichment in brain-derived molecules. A detailed structural analysis of brain and cerebrospinal fluid glycans collected in publications in healthy and neurodegenerative conditions was undertaken and data was compiled to create a browsable dedicated set in the GlyConnect database of glycoproteins (https://glyconnect.expasy.org/brain). The shared molecular composition of cerebrospinal fluid with brain enhances the likelihood of novel glycobiomarker discovery for neurodegeneration, which may aid in unveiling disease mechanisms, therefore, providing with novel therapeutic targets as well as diagnostic and progression monitoring tools.
Topics: Humans; Glycosylation; Neurodegenerative Diseases; Glycoproteins; Protein Processing, Post-Translational; Glycomics; Polysaccharides; Biomarkers
PubMed: 37348818
DOI: 10.1016/j.arr.2023.101991 -
Oncogene Jun 2023Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Understanding the cancer mechanisms provides novel diagnostic, prognostic, and... (Review)
Review
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Understanding the cancer mechanisms provides novel diagnostic, prognostic, and therapeutic markers for the management of HCC disease. In addition to genomic and epigenomic regulation, post-translational modification exerts a profound influence on protein functions and plays a critical role in regulating various biological processes. Protein glycosylation is one of the most common and complex post-translational modifications of newly synthesized proteins and acts as an important regulatory mechanism that is implicated in fundamental molecular and cell biology processes. Recent studies in glycobiology suggest that aberrant protein glycosylation in hepatocytes contributes to the malignant transformation to HCC by modulating a wide range of pro-tumorigenic signaling pathways. The dysregulated protein glycosylation regulates cancer growth, metastasis, stemness, immune evasion, and therapy resistance, and is regarded as a hallmark of HCC. Changes in protein glycosylation could serve as potential diagnostic, prognostic, and therapeutic factors in HCC. In this review, we summarize the functional importance, molecular mechanism, and clinical application of protein glycosylation alterations in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Glycosylation; Protein Processing, Post-Translational; Carcinogenesis; Proteins
PubMed: 37193819
DOI: 10.1038/s41388-023-02702-w