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Cell Death Discovery Aug 2023Alzheimer's disease (AD) is a chronic neurodegenerative disease that seriously endangers the physical and mental health of patients, however, there are still no... (Review)
Review
Alzheimer's disease (AD) is a chronic neurodegenerative disease that seriously endangers the physical and mental health of patients, however, there are still no effective drugs or methods to cure this disease up to now. Protein glycosylation is the most common modifications of the translated proteins in eukaryotic cells. Recently many researches disclosed that aberrant glycosylation happens in some important AD-related proteins, such as APP, Tau, Reelin and CRMP-2, etc, suggesting a close link between abnormal protein glycosylation and AD. Because of its complexity and diversity, glycosylation is thus considered a completely new entry point for understanding the precise cause of AD. This review comprehensively summarized the currently discovered changes in protein glycosylation patterns in AD, and especially introduced the latest progress on the mechanism of protein glycosylation affecting the progression of AD and the potential application of protein glycosylation in AD detection and treatment, thereby providing a wide range of opportunities for uncovering the pathogenesis of AD and promoting the translation of glycosylation research into future clinical applications.
PubMed: 37626031
DOI: 10.1038/s41420-023-01617-5 -
Journal of Translational Medicine Jun 2023Hepatocellular carcinoma (HCC) is one of the most lethal tumor types worldwide. Glycosylation has shown promise in the study of tumor mechanisms and treatment. The...
Hepatocellular carcinoma (HCC) is one of the most lethal tumor types worldwide. Glycosylation has shown promise in the study of tumor mechanisms and treatment. The glycosylation status of HCC and the underlying molecular mechanisms are still not fully elucidated. Using bioinformatic analysis we obtained a more comprehensive characterization of glycosylation of HCC. Our analysis presented that high glycosylation levels might correlate with tumor progression and poor prognosis. Subsequent Experiments identified key molecular mechanisms for ST6GALNAC4 promoting malignant progression by inducing abnormal glycosylation. We confirmed the contribution of ST6GALNAC4 to proliferation, migration, and invasion in vitro and in vivo. Mechanistic studies revealed that ST6GALNAC4 may be induced abnormal TGFBR2 glycosylation, resulting in the higher protein levels of TGFBR2 and TGF[Formula: see text] pathway increased activation. Our study also provided a further understand of immunosuppressive function of ST6GALNAC4 through T antigen-galectin3+ TAMs axis. This study has provided one such possibility that galectin3 inhibitors might be an acceptable treatment choice for HCC patients with high T antigen expression.
Topics: Humans; Antigens, Viral, Tumor; Carcinogenesis; Carcinoma, Hepatocellular; Glycosylation; Liver Neoplasms; Receptor, Transforming Growth Factor-beta Type II; Sialyltransferases
PubMed: 37381011
DOI: 10.1186/s12967-023-04191-7 -
Molecules (Basel, Switzerland) Oct 2023Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the... (Review)
Review
Mucin glycans are an important component of the mucus barrier and a vital defence against physical and chemical damage as well as pathogens. There are 20 mucins in the human body, which can be classified into secreted mucins and transmembrane mucins according to their distributions. The major difference between them is that secreted mucins do not have transmembrane structural domains, and the expression of each mucin is organ and cell-specific. Under physiological conditions, mucin glycans are involved in the composition of the mucus barrier and thus protect the body from infection and injury. However, abnormal expression of mucin glycans can lead to the occurrence of diseases, especially cancer, through various mechanisms. Therefore, targeting mucin glycans for the diagnosis and treatment of cancer has always been a promising research direction. Here, we first summarize the main types of glycosylation (O-GalNAc glycosylation and N-glycosylation) on mucins and the mechanisms by which abnormal mucin glycans occur. Next, how abnormal mucin glycans contribute to cancer development is described. Finally, we summarize MUC1-based antibodies, vaccines, radio-pharmaceuticals, and CAR-T therapies using the best characterized MUC1 as an example. In this section, we specifically elaborate on the recent new cancer therapy CAR-M, which may bring new hope to cancer patients.
Topics: Humans; Mucins; Mucin-1; Polysaccharides; Glycosylation; Neoplasms
PubMed: 37894512
DOI: 10.3390/molecules28207033 -
The Journal of Pathology Sep 2023Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour...
Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3F -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Male; Humans; Sialyltransferases; Prostatic Neoplasms; Glycosylation; Polysaccharides; United Kingdom; beta-D-Galactoside alpha 2-6-Sialyltransferase; Antigens, CD
PubMed: 37550801
DOI: 10.1002/path.6152 -
Glycobiology Dec 2023N-linked protein glycosylation is a post-translational modification that exists in all domains of life. It involves two consecutive steps: (i) biosynthesis of a... (Review)
Review
N-linked protein glycosylation is a post-translational modification that exists in all domains of life. It involves two consecutive steps: (i) biosynthesis of a lipid-linked oligosaccharide (LLO), and (ii) glycan transfer from the LLO to asparagine residues in secretory proteins, which is catalyzed by the integral membrane enzyme oligosaccharyltransferase (OST). In the last decade, structural and functional studies of the N-glycosylation machinery have increased our mechanistic understanding of the pathway. The structures of bacterial and eukaryotic glycosyltransferases involved in LLO elongation provided an insight into the mechanism of LLO biosynthesis, whereas structures of OST enzymes revealed the molecular basis of sequon recognition and catalysis. In this review, we will discuss approaches used and insight obtained from these studies with a special emphasis on the design and preparation of substrate analogs.
Topics: Glycosylation; Hexosyltransferases; Lipopolysaccharides; Polysaccharides; Glycosyltransferases
PubMed: 37399117
DOI: 10.1093/glycob/cwad053 -
The Journal of Biological Chemistry Jul 2023A primary pathology of Alzheimer's disease (AD) is amyloid β (Aβ) deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy...
A primary pathology of Alzheimer's disease (AD) is amyloid β (Aβ) deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal Aβ precursor protein (APP). Although vascular amyloid deposits' origins remain unclear, endothelial APP expression in APP knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APP's importance. Furthermore, two types of endothelial APP-highly O-glycosylated APP and hypo-O-glycosylated APP-have been biochemically identified, but only the former is cleaved for Aβ production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that hypo-O-glycosylated APP is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires additional O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced Aβ production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Cerebral Amyloid Angiopathy; Endothelial Cells; Glycosylation; Protein Transport; Neurons; Golgi Apparatus; Acetylgalactosamine
PubMed: 37302553
DOI: 10.1016/j.jbc.2023.104905 -
Analytical Biochemistry Jul 2023Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD...
Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues - one in the hinge region and one in the C-terminal region - and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD.
Topics: Aged; Aged, 80 and over; Humans; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Apolipoproteins E; Biomarkers; Chromatography, Liquid; Genotype; Glycosylation; Peptide Fragments; Plaque, Amyloid; Tandem Mass Spectrometry
PubMed: 37072097
DOI: 10.1016/j.ab.2023.115156 -
Journal of Experimental & Clinical... Nov 2023Recent evidence reveals the emerging functions of circular RNA (circRNA) and protein glycosylation in cancer progression. However, the roles of circRNA in regulating...
BACKGROUND
Recent evidence reveals the emerging functions of circular RNA (circRNA) and protein glycosylation in cancer progression. However, the roles of circRNA in regulating glycosyltransferase expression in gastric cancer remain to be determined.
METHODS
Circular RNAs (circRNAs) were validated by Sanger sequencing. Co-immunoprecipitation, mass spectrometry, and RNA sequencing assays were applied to explore protein interaction and target genes. Gene expression regulation was observed by chromatin immunoprecipitation, RNA immunoprecipitation, dual-luciferase reporter, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA and its partners on the glycosylation, growth, invasion, and metastasis of gastric cancer cells.
RESULTS
Circ-hnRNPU, an exonic circRNA derived from heterogenous nuclear ribonuclear protein U (hnRNPU), was identified to exert tumor suppressive roles in protein glycosylation and progression of gastric cancer. Mechanistically, circ-hnRNPU physically interacted with non-POU domain containing octamer binding (NONO) protein to induce its cytoplasmic retention, resulting in down-regulation of glycosyltransferases (GALNT2, GALNT6, MGAT1) and parental gene hnRNPU via repression of nuclear NONO-mediated c-Myc transactivation or cytoplasmic NONO-facilitated mRNA stability. Rescue studies indicated that circ-hnRNPU inhibited the N- and O-glycosylation, growth, invasion, and metastasis of gastric cancer cells via interacting with NONO protein. Pre-clinically, administration of lentivirus carrying circ-hnRNPU suppressed the protein glycosylation, tumorigenesis, and aggressiveness of gastric cancer xenografts. In clinical cases, low circ-hnRNPU levels and high NONO or c-Myc expression were associated with poor survival outcome of gastric cancer patients.
CONCLUSIONS
These findings indicate that circ-hnRNPU inhibits NONO-mediated c-Myc transactivation and mRNA stabilization essential for glycosylation and cancer progression.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Glycosylation; MicroRNAs; Nuclear Proteins; RNA, Circular; RNA, Messenger; RNA-Binding Proteins; Stomach Neoplasms; Transcription Factors; Transcriptional Activation
PubMed: 37993881
DOI: 10.1186/s13046-023-02898-5 -
Biomolecules Mar 2024Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement... (Review)
Review
Diabetes and its associated complications have increasingly become major challenges for global healthcare. The current therapeutic strategies involve insulin replacement therapy for type 1 diabetes (T1D) and small-molecule drugs for type 2 diabetes (T2D). Despite these advances, the complex nature of diabetes necessitates innovative clinical interventions for effective treatment and complication prevention. Accumulative evidence suggests that protein post-translational modifications (PTMs), including glycosylation, phosphorylation, acetylation, and SUMOylation, play important roles in diabetes and its pathological consequences. Therefore, the investigation of these PTMs not only sheds important light on the mechanistic regulation of diabetes but also opens new avenues for targeted therapies. Here, we offer a comprehensive overview of the role of several PTMs in diabetes, focusing on the most recent advances in understanding their functions and regulatory mechanisms. Additionally, we summarize the pharmacological interventions targeting PTMs that have advanced into clinical trials for the treatment of diabetes. Current challenges and future perspectives are also provided.
Topics: Humans; Diabetes Mellitus, Type 2; Protein Processing, Post-Translational; Phosphorylation; Glycosylation; Sumoylation
PubMed: 38540730
DOI: 10.3390/biom14030310 -
Nature Communications Mar 2024Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered...
Host survival depends on the elimination of virus and mitigation of tissue damage. Herein, we report the modulation of D-mannose flux rewires the virus-triggered immunometabolic response cascade and reduces tissue damage. Safe and inexpensive D-mannose can compete with glucose for the same transporter and hexokinase. Such competitions suppress glycolysis, reduce mitochondrial reactive-oxygen-species and succinate-mediated hypoxia-inducible factor-1α, and thus reduce virus-induced proinflammatory cytokine production. The combinatorial treatment by D-mannose and antiviral monotherapy exhibits in vivo synergy despite delayed antiviral treatment in mouse model of virus infections. Phosphomannose isomerase (PMI) knockout cells are viable, whereas addition of D-mannose to the PMI knockout cells blocks cell proliferation, indicating that PMI activity determines the beneficial effect of D-mannose. PMI inhibition suppress a panel of virus replication via affecting host and viral surface protein glycosylation. However, D-mannose does not suppress PMI activity or virus fitness. Taken together, PMI-centered therapeutic strategy clears virus infection while D-mannose treatment reprograms glycolysis for control of collateral damage.
Topics: Animals; Mice; Mannose-6-Phosphate Isomerase; Glycosylation; Mannose; Glucose; Antiviral Agents
PubMed: 38459021
DOI: 10.1038/s41467-024-46415-4