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International Journal of Molecular... Mar 2024Glycosylation plays a crucial role in the maintenance of homeostasis in the body and at the onset of diseases such as inflammation, neurodegeneration, infection,... (Review)
Review
Glycosylation plays a crucial role in the maintenance of homeostasis in the body and at the onset of diseases such as inflammation, neurodegeneration, infection, diabetes, and cancer. It is also involved in bone metabolism. - and -glycans have been shown to regulate osteoblast and osteoclast differentiation. We recently demonstrated that ganglio-series and globo-series glycosphingolipids were essential for regulating the proliferation and differentiation of osteoblasts and osteoclasts in glycosyltransferase-knockout mice. Herein, we reviewed the importance of the regulation of bone metabolism by glycoconjugates, such as glycolipids and glycoproteins, including our recent results.
Topics: Animals; Mice; Glycosylation; Homeostasis; Glycosyltransferases; Glycolipids; Inflammation; Mice, Knockout
PubMed: 38612379
DOI: 10.3390/ijms25073568 -
Analytical Chemistry Sep 2023Altered protein glycosylation is typically associated with cognitive defects and other phenotypes, but there is a lack of knowledge about the brain glycoproteome. Here,...
Altered protein glycosylation is typically associated with cognitive defects and other phenotypes, but there is a lack of knowledge about the brain glycoproteome. Here, we used the newly available -glycoprotease IMPa from for comprehensive -glycoproteomic analyses of the mouse brain. In this approach, total tryptic glycopeptides were prepared, extracted, purified, and conjugated to a solid support before an enzymatic cleavage by IMPa. -glycopeptides were analyzed by electron-transfer/higher-energy collision dissociation (EThcD), which permits site-specific and global analysis of all types of -glycans. We developed two complementary approaches for the analysis of the total -glycoproteome using HEK293 cells and derivatives. The results demonstrated that IMPa and EThcD facilitate the confident localization of -glycans on glycopeptides. We then applied these approaches to characterize the -glycoproteome of the mouse brain, which revealed the high frequency of various sialylated -glycans along with the unusual presence of the Tn antigen. Unexpectedly, the results demonstrated that glycoproteins in the brain -glycoproteome only partly overlap with those reported for the brain -glycoproteome. These approaches will aid in identifying the novel -glycoproteomes of different cells and tissues and foster clinical and translational insights into the functions of protein -glycosylation in the brain and other organs.
Topics: Humans; Animals; Mice; HEK293 Cells; Brain; Electron Transport; Glycopeptides; Proteome
PubMed: 37624755
DOI: 10.1021/acs.analchem.3c00408 -
Frontiers in Immunology 2023The immune system is strictly regulated by glycosylation through the addition of highly diverse and dynamically changing sugar structures (glycans) to the majority of... (Review)
Review
The immune system is strictly regulated by glycosylation through the addition of highly diverse and dynamically changing sugar structures (glycans) to the majority of immune cell receptors. Although knowledge in the field of glycoimmunology is still limited, numerous studies point to the key role of glycosylation in maintaining homeostasis, but also in reflecting its disruption. Changes in oligosaccharide patterns can lead to impairment of both innate and acquired immune responses, with important implications in the pathogenesis of diseases, including autoimmunity. B cells appear to be unique within the immune system, since they exhibit both innate and adaptive immune activity. B cell surface is rich in glycosylated proteins and lectins which recognise glycosylated ligands on other cells. Glycans are important in the development, selection, and maturation of B cells. Changes in sialylation and fucosylation of cell surface proteins affect B cell signal transduction through BCRs, CD22 inhibitory coreceptor and Siglec-G. Plasmocytes, as the final stage of B cell differentiation, produce and secrete immunoglobulins (Igs), of which IgGs are the most abundant -glycosylated proteins in human serum with the conserved -glycosylation site at Asn297. -oligosaccharide composition of the IgG Fc region affects its secretion, structure, half-life and effector functions (ADCC, CDC). IgG -glycosylation undergoes little change during homeostasis, and may gradually be modified with age and during ongoing inflammatory processes. Hyperactivated B lymphocytes secrete autoreactive antibodies responsible for the development of autoimmunity. The altered profile of IgG -glycans contributes to disease progression and remission and is sensitive to the application of therapeutic substances and immunosuppressive agents. In this review, we focus on the role of -glycans in B-cell biology and IgG activity, the rearrangement of IgG oligosaccharides in aging, autoimmunity and immunosuppressive therapy.
Topics: Humans; Glycosylation; Immunoglobulin G; Autoimmunity; B-Lymphocytes; Polysaccharides; Oligosaccharides; Anti-Inflammatory Agents
PubMed: 37575234
DOI: 10.3389/fimmu.2023.1188838 -
Frontiers in Immunology 2023The coronavirus disease 2019 (COVID-19) pandemic has exerted a profound influence on humans. Increasing evidence shows that immune response is crucial in influencing the...
BACKGROUND
The coronavirus disease 2019 (COVID-19) pandemic has exerted a profound influence on humans. Increasing evidence shows that immune response is crucial in influencing the risk of infection and disease severity. Observational studies suggest an association between COVID-19 and immunoglobulin G (IgG) N-glycosylation traits, but the causal relevance of these traits in COVID-19 susceptibility and severity remains controversial.
METHODS
We conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between 77 IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity using summary-level data from genome-wide association studies (GWAS) and applying multiple methods including inverse-variance weighting (IVW), MR Egger, and weighted median. We also used Cochran's Q statistic and leave-one-out analysis to detect heterogeneity across each single nucleotide polymorphism (SNP). Additionally, we used the MR-Egger intercept test, MR-PRESSO global test, and PhenoScanner tool to detect and remove SNPs with horizontal pleiotropy and to ensure the reliability of our results.
RESULTS
We found significant causal associations between genetically predicted IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity. Specifically, we observed reduced risk of COVID-19 with the genetically predicted increased IgG N-glycan trait IGP45 (OR = 0.95, 95% CI = 0.92-0.98; FDR = 0.019). IGP22 and IGP30 were associated with a higher risk of COVID-19 hospitalization and severity. Two (IGP2 and IGP77) and five (IGP10, IGP14, IGP34, IGP36, and IGP50) IgG N-glycosylation traits were causally associated with a decreased risk of COVID-19 hospitalization and severity, respectively. Sensitivity analyses did not identify any horizontal pleiotropy.
CONCLUSIONS
Our study provides evidence that genetically elevated IgG N-glycosylation traits may have a causal effect on diverse COVID-19 outcomes. Our findings have potential implications for developing targeted interventions to improve COVID-19 outcomes by modulating IgG N-glycosylation levels.
Topics: Humans; Glycosylation; COVID-19; Genome-Wide Association Study; Mendelian Randomization Analysis; Reproducibility of Results; Immunoglobulin G
PubMed: 37662938
DOI: 10.3389/fimmu.2023.1217444 -
Cell Death & Disease Oct 2023Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo...
Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo implantation, and dysfunction causes pregnancy failure. Protein glycosylation plays crucial roles in reproduction. However, it remains unclear whether the glycosylation of trophoblasts is involved in trophoblast migration and invasion processes during embryo implantation failure. By Lectin array, we discovered the decreased α1,3-fucosylation, especially difucosylated Lewis Y (LeY) glycan, in the villus tissues of miscarriage patients when compared with normal pregnancy women. Downregulating LeY biosynthesis by silencing the key enzyme fucosyltransferase IV (FUT4) inhibited migration and invasion ability of trophoblast cells. Using proteomics and translatomics, the specific LeY scaffolding glycoprotein of mesoderm-specific transcript (MEST) with glycosylation site at Asn163 was identified, and its expression enhanced migration and invasion ability of trophoblast cells. The results also provided novel evidence showing that decreased LeY modification on MEST hampered the binding of MEST with translation factor eIF4E2, and inhibited implantation-related gene translation initiation, which caused pregnancy failure. The α1,3-fucosylation of MEST by FUT4 may serve as a new biomarker for evaluating the functional state of pregnancy, and a target for infertility treatment.
Topics: Pregnancy; Humans; Female; Glycosylation; Trophoblasts; Embryo Implantation; Epithelial Cells; Biomarkers; Fucosyltransferases
PubMed: 37798282
DOI: 10.1038/s41419-023-06166-4 -
Frontiers in Immunology 2023Unlike glycosylation of proteins expressed in mammalian systems, bacterial glycosylation is often neglected in the development of recombinant vaccines.
INTRODUCTION
Unlike glycosylation of proteins expressed in mammalian systems, bacterial glycosylation is often neglected in the development of recombinant vaccines.
METHODS
Here, we compared the effects of glycosylation of YghJ, an protein important for mucus attachment of bacteria causing in urinary tract infections (UTIs). A novel method based on statistical evaluation of phage display for the identification and comparison of epitopes and mimotopes of anti-YghJ antibodies in the sera was used. This is the first time that the effect of glycosylation of a recombinant bacterial antigen has been studied at the peptide epitope level.
RESULTS
The study identifies differences in the immune response for (non)-glycosylated antigens in rabbits and pigs and compares them to a large group of patients with UTI, which have been diagnosed as positive for various bacterial pathogens. We identified glycosylation-specific peptide epitopes, a large immunological similarity between different UTI pathogens, and a broad peptide epitope pattern in patients and animals, which could result in a variable response in patients upon vaccination.
DISCUSSION
This epitope analysis indicates that the vaccination of rabbits and pigs raises antibodies that translate well into the human immune system. This study underlines the importance of glycosylation in bacterial vaccines and provides detailed immune diagnostic methods to understand individual immune responses to vaccines.
Topics: Humans; Rabbits; Swine; Animals; Epitopes; Antigens, Bacterial; Glycosylation; Escherichia coli; Urinary Tract Infections; Peptides; Mammals; Escherichia coli Proteins; Metalloproteases
PubMed: 37954588
DOI: 10.3389/fimmu.2023.1258136 -
Frontiers in Cellular and Infection... 2024The genus , which colonizes mucosal surfaces, includes both commensal and pathogenic species that are exclusive to humans. The two pathogenic species are closely... (Review)
Review
The genus , which colonizes mucosal surfaces, includes both commensal and pathogenic species that are exclusive to humans. The two pathogenic species are closely related but cause quite different diseases, meningococcal sepsis and meningitis () and sexually transmitted gonorrhea ). Although obvious differences in bacterial niches and mechanisms for transmission exists, pathogenic have high levels of conservation at the levels of nucleotide sequences, gene content and synteny. Species of express broad-spectrum -linked protein glycosylation where the glycoproteins are largely transmembrane proteins or lipoproteins localized on the cell surface or in the periplasm. There are diverse functions among the identified glycoproteins, for example type IV biogenesis proteins, proteins involved in antimicrobial resistance, as well as surface proteins that have been suggested as vaccine candidates. The most abundant glycoprotein, PilE, is the major subunit of pili which are an important colonization factor. The glycans attached can vary extensively due to phase variation of protein glycosylation ( genes and polymorphic gene content. The exact roles of glycosylation in remains to be determined, but increasing evidence suggests that glycan variability can be a strategy to evade the human immune system. In addition, pathogenic and commensal appear to have significant glycosylation differences. Here, the current knowledge and implications of protein glycosylation genes, glycan diversity, glycoproteins and immunogenicity in pathogenic are summarized and discussed.
Topics: Humans; Bacterial Proteins; Glycoproteins; Glycosylation; Neisseria gonorrhoeae; Neisseria meningitidis; Polysaccharides; Meningitis, Meningococcal; Gonorrhea
PubMed: 38808060
DOI: 10.3389/fcimb.2024.1407863 -
Biomedicine & Pharmacotherapy =... Oct 2023Mammarenaviruses are enveloped RNA viruses that can be associated with rodent-transmitted diseases in humans. Their virions are composed of a nucleocapsid surrounded by... (Review)
Review
Mammarenaviruses are enveloped RNA viruses that can be associated with rodent-transmitted diseases in humans. Their virions are composed of a nucleocapsid surrounded by a lipid bilayer with glycoprotein (GP) spikes interacting with receptors on target cells. Both the GP and receptors are highly glycosylated, with glycosylation patterns being crucial for virus binding and cell entry, viral tropism, immune responses, or therapy strategies. These effects have been previously described for several different viruses. In case of arenaviruses, they remain insufficiently understood. Thus, it is important to determine the mechanisms of glycosylation of viral proteins and receptors responsible for infection, in order to fully understand the biology of arenaviruses. In this article, we have summarized and critically evaluated the available literature data on the glycosylation of mammarenavirus-associated proteins to facilitate further research in this field.
Topics: Humans; Glycosylation; Virus Internalization; Receptors, Cell Surface; Arenaviridae Infections; Glycoproteins
PubMed: 37586116
DOI: 10.1016/j.biopha.2023.115196 -
Biochimica Et Biophysica Acta.... Aug 2023Golgi cation homeostasis is known to be crucial for many cellular processes including vesicular fusion events, protein secretion, as well as for the activity of Golgi...
Golgi cation homeostasis is known to be crucial for many cellular processes including vesicular fusion events, protein secretion, as well as for the activity of Golgi glycosyltransferases and glycosidases. TMEM165 was identified in 2012 as the first cation transporter related to human glycosylation diseases, namely the Congenital Disorders of Glycosylation (CDG). Interestingly, divalent manganese (Mn) supplementation has been shown to suppress the observed glycosylation defects in TMEM165-deficient cell lines, thus suggesting that TMEM165 is involved in cellular Mn homeostasis. This paper demonstrates that the origin of the Golgi glycosylation defects arises from impaired Golgi Mn homeostasis in TMEM165-depleted cells. We show that Mn supplementation fully rescues the Mn content in the secretory pathway/organelles of TMEM165-depleted cells and hence the glycosylation process. Strong cytosolic and organellar Mn accumulations can also be observed in TMEM165- and SPCA1-depleted cells upon incubation with increasing Mn concentrations, thus demonstrating the crucial involvement of these two proteins in cellular Mn homeostasis. Interestingly, our results show that the cellular Mn homeostasis maintenance in control cells is correlated with the presence of TMEM165 and that the Mn-detoxifying capacities of cells, through the activity of SPCA1, rely on the Mn-induced degradation mechanism of TMEM165. Finally, this paper highlights that TMEM165 is essential in secretory pathway/organelles Mn homeostasis maintenance to ensure both Golgi glycosylation enzyme activities and cytosolic Mn detoxification.
Topics: Humans; Manganese; Cation Transport Proteins; Antiporters; Golgi Apparatus; Homeostasis
PubMed: 37062452
DOI: 10.1016/j.bbadis.2023.166717 -
Biotechnology Advances Oct 2023Protein glycosylation has a huge impact on biological processes in all domains of life. The type of glycan present on a recombinant glycoprotein depends on protein... (Review)
Review
Protein glycosylation has a huge impact on biological processes in all domains of life. The type of glycan present on a recombinant glycoprotein depends on protein intrinsic features and the glycosylation repertoire of the cell type used for expression. Glycoengineering approaches are used to eliminate unwanted glycan modifications and to facilitate the coordinated expression of glycosylation enzymes or whole metabolic pathways to furnish glycans with distinct modifications. The formation of tailored glycans enables structure-function studies and optimization of therapeutic proteins used in different applications. While recombinant proteins or proteins from natural sources can be in vitro glycoengineered using glycosyltransferases or chemoenzymatic synthesis, many approaches use genetic engineering involving the elimination of endogenous genes and introduction of heterologous genes to cell-based production systems. Plant glycoengineering enables the in planta production of recombinant glycoproteins with human or animal-type glycans that resemble natural glycosylation or contain novel glycan structures. This review summarizes key achievements in glycoengineering of plants and highlights current developments aiming to make plants more suitable for the production of a diverse range of recombinant glycoproteins for innovative therapies.
Topics: Animals; Humans; Glycosylation; Plants; Recombinant Proteins; Vaccines; Polysaccharides; Glycoproteins
PubMed: 37315875
DOI: 10.1016/j.biotechadv.2023.108197