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Protein Glycosylation and Human Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Carbohydrates".

Deadline for manuscript submissions: closed (10 December 2023) | Viewed by 19487

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Special Issue Editors

Prof. Dr. Gordan Lauc

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Department of Biochemistry and Molecular Biology, University of Zagreb, Ante Kovačića 1, 10000 Zagreb, Croatia
Interests: glycosylation; glycobiology; glycomics; immunity; immunoglobulin G; biomarker

Dr. Maja Pucic Bakovic

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Genos Glycoscience Research Laboratory, 10000 Zagreb, Croatia
Interests: glycomics, glycoproteomics; glycosylation

Dr. Ivan Gudelj

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Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
Interests: protein glycosylation; glycosylation; glycomics; glycan

Dr. Tamara Štambuk

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Genos Glycoscience Research Laboratory, 10000 Zagreb, Croatia
Interests: glycobiology; protein glycosylation; glycomics; immunoglobulin G; biomarker

Special Issue Information

Dear Colleagues,

Glycosylation is the most diverse posttranslational protein modification and is profoundly involved in a plethora of biological processes, including disease development and aggravation. Despite recent analytical developments, many aspects of the glycosylation process still remain unknown, both in health and disease. Contrary to genetic biomarkers, which are set for a lifetime, human glycome is dynamic and undergoes changes in response to physiological triggers, immune challenges and pathophysiological processes. Thus, most human diseases, including inflammatory, autoimmune, infectious and cardiometabolic diseases, and cancer, show associations with specific changes in glycan composition that often precede disease onset. As the structural diversity of glycome represents a complex pool of information, glycosylation changes can be specific for the disease and/or disease stage, which makes them valuable diagnostic and prognostic markers as well as a target for therapeutic interventions.

In this context, this Special Issue is collecting research articles and targeted reviews that address the most recent advances related to protein glycosylation in common complex diseases. Contributions that cover the development and improvements of analytical approaches for glycosylation analysis are very welcome, as well as research describing applications of state-of-the-art glycoprofiling methods and technologies in monitoring glycosylation pattern changes during disease development, progression and intervention (e.g., response to therapy, lifestyle changes). Finally, we welcome new insights that elucidate the structural and functional implications of glycoprotein heterogeneity in complex pathologies.

Prof. Dr. Gordan Lauc
Dr. Maja Pucic Bakovic
Dr. Ivan Gudelj
Dr. Tamara Štambuk
Guest Editors

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Keywords

glyco(proteo)mics
glycosylation in diseases (inflammatory, cardiovascular, metabolic)
biomarker discovery

Published Papers (10 papers)

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Research

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14 pages, 3249 KiB

Open AccessArticle

Aberrant Mannosylated and Highly Fucosylated Glycoepitopes of Prostatic Acid Phosphatase as Potential Ligands for Dendritic-Cell Specific ICAM-Grabbing Nonintegrin (DC-SIGN) in Human Seminal Plasma—A Step towards Explaining Idiopathic Infertility

by Anna Kałuża, Katarzyna Trzęsicka, Damian Drzyzga and Mirosława Ferens-Sieczkowska

Biomolecules 2024, 14(1), 58; https://doi.org/10.3390/biom14010058 - 31 Dec 2023

Viewed by 1062

Abstract

Semen prostatic acid phosphatase (PAP) has been proposed as an endogenous ligand for dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), which plays a critical immuno-modulating role in maintaining homeostasis in the female reproductive tracts. In the current study, we assumed that semen PAP bears a set of fucosylated and mannosylated glycans, which may mediate the efficient binding of PAP to DC-SIGN. To investigate this hypothesis, we developed ELISA assays using Galanthus nivalis and Lotus tetragonolobus lectins capable of binding mannose-containing glycans or LewisX and LewisY motifs, respectively. In our assay with Galanthus nivalis, we detected that the relative reactivity of PAP mannose-presenting glycans in the normozoospermic idiopathic group was significantly higher than in the asthenozoospermic, oligozoospermic and oligoasthenozoospermic groups. Simultaneously, we observed slight differences in the relative reactivities of PAP glycans with Lotus tetragonolobus lectin among groups of patients with abnormal semen parameters. Subsequently, we examined whether DC-SIGN interacts with seminal plasma PAP glycans, and we detected a significantly higher relative reactivity in the normozoospermic group compared to the oligozoospermic group. Finally, we concluded that the significantly aberrant abundance of mannosylated functional groups of PAP among patients with semen disorders can suggest that PAP may thereby be engaged in modulating the immune response and promoting a tolerogenic response to male antigens in the female reproductive system. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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19 pages, 2591 KiB

Open AccessArticle

by Óscar Lado-Baleato, Jorge Torre, Róisín O’Flaherty, Manuela Alonso-Sampedro, Iago Carballo, Carmen Fernández-Merino, Carmen Vidal, Francisco Gude, Radka Saldova and Arturo González-Quintela

Biomolecules 2024, 14(1), 17; https://doi.org/10.3390/biom14010017 - 22 Dec 2023

Cited by 1 | Viewed by 941

Abstract

(1) Aim: To describe, in a general adult population, the serum N-glycome in relation to age in men and women, and investigate the association of N-glycome patterns with age-related comorbidity; (2) Methods: The serum N-glycome was studied by hydrophilic interaction chromatography with ultra-performance liquid chromatography in 1516 randomly selected adults (55.3% women; age range 18–91 years). Covariates included lifestyle factors, metabolic disorders, inflammatory markers, and an index of comorbidity. Principal component analysis was used to define clusters of individuals based on the 46 glycan peaks obtained in chromatograms; (3) Results: The serum N-glycome changed with ageing, with significant differences between men and women, both in individual N-glycan peaks and in groups defined by common features (branching, galactosylation, sialylation, fucosylation, and oligomannose). Through K-means clustering algorithm, the individuals were grouped into a cluster characterized by abundance of simpler N-glycans and a cluster characterized by abundance of higher-order N-glycans. The individuals of the first cluster were older, showed higher concentrations of glucose and glycation markers, higher levels of some inflammatory markers, lower glomerular filtration rate, and greater comorbidity index; (4) Conclusions: The serum N-glycome changes with ageing with sex dimorphism. The N-glycome could be, in line with the inflammaging hypothesis, a marker of unhealthy aging. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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17 pages, 1341 KiB

Open AccessEditor’s ChoiceArticle

Long-Term Culturing of FreeStyle 293-F Cells Affects Immunoglobulin G Glycome Composition

by Fran Lukšić, Anika Mijakovac, Goran Josipović, Vedrana Vičić Bočkor, Jasminka Krištić, Ana Cindrić, Martina Vinicki, Filip Rokić, Oliver Vugrek, Gordan Lauc and Vlatka Zoldoš

Biomolecules 2023, 13(8), 1245; https://doi.org/10.3390/biom13081245 - 14 Aug 2023

Viewed by 1509

Abstract

Glycosylation of IgG regulates the effector function of this antibody in the immune response. Glycosylated IgG is a potent therapeutic used for both research and clinical purposes. While there is ample research on how different cell culture conditions affect IgG glycosylation, the data are missing on the stability of IgG glycome during long cell passaging, i.e., cell “aging”. To test this, we performed three independent time course experiments in FreeStyle 293-F cells, which secrete IgG with a human-like glycosylation pattern and are frequently used to generate defined IgG glycoforms. During long-term cell culturing, IgG glycome stayed fairly stable except for galactosylation, which appeared extremely variable. Cell transcriptome analysis revealed no correlation in galactosyltransferase B4GALT1 expression with galactosylation change, but with expression of EEF1A1 and SLC38A10, genes previously associated with IgG galactosylation through GWAS. The FreeStyle 293-F cell-based system for IgG production is a good model for studies of mechanisms underlying IgG glycosylation, but results from the present study point to the utmost importance of the need to control IgG galactosylation in both in vitro and in vivo systems. This is especially important for improving the production of precisely glycosylated IgG for therapeutic purposes, since IgG galactosylation affects the inflammatory potential of IgG. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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10 pages, 1211 KiB

Open AccessEditor’s ChoiceArticle

An Integrated Glycosylation Signature of Rheumatoid Arthritis

by Oleg A. Mayboroda, Guinevere S. M. Lageveen-Kammeijer, Manfred Wuhrer and Radboud J. E. M. Dolhain

Biomolecules 2023, 13(7), 1106; https://doi.org/10.3390/biom13071106 - 12 Jul 2023

Viewed by 1072

Abstract

Rheumatoid arthritis (RA) Is a highly prevalent autoimmune disease that affects the joints but also various other organs. The disease is characterized by autoantibodies that are often already observed pre-disease. Since the 1980s, it has been known that antibody glycosylation is different in RA as compared to control individuals. While the literature on glycosylation changes in RA is dominated by reports on serum or plasma immunoglobulin G (IgG), our recent studies have indicated that the glycosylation changes observed for immunoglobulin A (IgA) and total serum N-glycome (TSNG) may be similarly prominent, and useful in differentiating between the RA patients and controls, or as a proxy of the disease activity. In this study, we integrated and compared the RA glycosylation signatures of IgG, IgA and TSNG, all determined in the pregnancy-induced amelioration of rheumatoid arthritis (PARA) cohort. We assessed the association of the altered glycosylation patterns with the disease, autoantibody positivity and disease activity. Our analyses indicated a common, composite glycosylation signature of RA that was independent of the autoantibody status. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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18 pages, 2907 KiB

Open AccessEditor’s ChoiceArticle

Serum N-Glycosylation RPLC-FD-MS Assay to Assess Colorectal Cancer Surgical Interventions

by Alan B. Moran, Georgia Elgood-Hunt, Yuri E. M. van der Burgt, Manfred Wuhrer, Wilma E. Mesker, Rob A. E. M. Tollenaar, Daniel I. R. Spencer and Guinevere S. M. Lageveen-Kammeijer

Biomolecules 2023, 13(6), 896; https://doi.org/10.3390/biom13060896 - 27 May 2023

Cited by 1 | Viewed by 2077

Abstract

A newly developed analytical strategy was applied to profile the total serum N-glycome of 64 colorectal cancer (CRC) patients before and after surgical intervention. In this cohort, it was previously found that serum N-glycome alterations in CRC were associated with patient survival. Here, fluorescent labeling of serum N-glycans was applied using procainamide and followed by sialic acid derivatization specific for α2,6- and α2,3-linkage types via ethyl esterification and amidation, respectively. This strategy allowed efficient separation of specific positional isomers on reversed-phase liquid chromatography–fluorescence detection–mass spectrometry (RPLC-FD-MS) and complemented the previous glycomics data based on matrix-assisted laser desorption/ionization (MALDI)-MS that did not include such separations. The results from comparing pre-operative CRC to post-operative samples were in agreement with studies that identified a decrease in di-antennary structures with core fucosylation and an increase in sialylated tri- and tetra-antennary N-glycans in CRC patient sera. Pre-operative abundances of N-glycans showed good performance for the classification of adenocarcinoma and led to the revisit of the previous MALDI-MS dataset with regard to histological and clinical data. This strategy has the potential to monitor patient profiles before, during, and after clinical events such as treatment, therapy, or surgery and should also be further explored. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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14 pages, 1009 KiB

Open AccessArticle

Physical Exercise Induces Significant Changes in Immunoglobulin G N-Glycan Composition in a Previously Inactive, Overweight Population

by Nina Šimunić-Briški, Robert Zekić, Vedran Dukarić, Mateja Očić, Azra Frkatović-Hodžić, Helena Deriš, Gordan Lauc and Damir Knjaz

Biomolecules 2023, 13(5), 762; https://doi.org/10.3390/biom13050762 - 27 Apr 2023

Cited by 2 | Viewed by 2273

Abstract

Regular exercise improves health, modulating the immune system and impacting inflammatory status. Immunoglobulin G (IgG) N-glycosylation reflects changes in inflammatory status; thus, we investigated the impact of regular exercise on overall inflammatory status by monitoring IgG N-glycosylation in a previously inactive, middle-aged, overweight and obese population (50.30 ± 9.23 years, BMI 30.57 ± 4.81). Study participants (N = 397) underwent one of three different exercise programs lasting three months with blood samples collected at baseline and at the end of intervention. After chromatographically profiling IgG N-glycans, linear mixed models with age and sex adjustment were used to investigate exercise effects on IgG glycosylation. Exercise intervention induced significant changes in IgG N-glycome composition. We observed an increase in agalactosylated, monogalctosylated, asialylated and core-fucosylated N-glycans (padj = 1.00 × 10⁻⁴, 2.41 × 10⁻²⁵, 1.51 × 10⁻²¹ and 3.38 × 10⁻³⁰, respectively) and a decrease in digalactosylated, mono- and di-sialylated N-glycans (padj = 4.93 × 10⁻¹², 7.61 × 10⁻⁹ and 1.09 × 10⁻²⁸, respectively). We also observed a significant increase in GP9 (glycan structure FA2[3]G1, β = 0.126, padj = 2.05 × 10⁻¹⁶), previously reported to have a protective cardiovascular role in women, highlighting the importance of regular exercise for cardiovascular health. Other alterations in IgG N-glycosylation reflect an increased pro-inflammatory IgG potential, expected in a previously inactive and overweight population, where metabolic remodeling is in the early stages due to exercise introduction. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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15 pages, 1000 KiB

Open AccessArticle

The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation

by Branimir Plavša, Janko Szavits-Nossan, Aleksandar Blivajs, Borna Rapčan, Barbara Radovani, Igor Šesto, Krešimir Štambuk, Vito Mustapić, Lovorka Đerek, Diana Rudan, Gordan Lauc and Ivan Gudelj

Biomolecules 2023, 13(4), 605; https://doi.org/10.3390/biom13040605 - 28 Mar 2023

Cited by 4 | Viewed by 1941

Abstract

Atrial fibrillation is a disease with a complex pathophysiology, whose occurrence and persistence are caused not only by aberrant electrical signaling in the heart, but by the development of a susceptible heart substrate. These changes, such as the accumulation of adipose tissue and interstitial fibrosis, are characterized by the presence of inflammation. N-glycans have shown great promise as biomarkers in different diseases, specifically those involving inflammatory changes. To assess the changes in the N-glycosylation of the plasma proteins and IgG in atrial fibrillation, we analyzed the N-glycosylation of 172 patients with atrial fibrillation, before and six months after a pulmonary vein isolation procedure, with 54 cardiovascularly healthy controls. An analysis was performed using ultra-high-performance liquid chromatography. We found one oligomannose N-glycan structure from the plasma N-glycome and six IgG N-glycans, mainly revolving around the presence of bisecting N-acetylglucosamine, that were significantly different between the case and control groups. In addition, four plasma N-glycans, mostly oligomannose structures and a derived trait that was related to them, were found to be different in the patients who experienced an atrial fibrillation recurrence during the six-month follow-up. IgG N-glycosylation was extensively associated with the CHA₂DS₂-VASc score, confirming its previously reported associations with the conditions that make up the score. This is the first study looking at the N-glycosylation patterns in atrial fibrillation and warrants further investigation into the prospect of glycans as biomarkers for atrial fibrillation. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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13 pages, 2419 KiB

Open AccessFeature PaperArticle

IgG N-Glycosylation Is Altered in Coronary Artery Disease

by Barbara Radovani, Frano Vučković, Aldo P. Maggioni, Ele Ferrannini, Gordan Lauc and Ivan Gudelj

Biomolecules 2023, 13(2), 375; https://doi.org/10.3390/biom13020375 - 16 Feb 2023

Cited by 6 | Viewed by 2515

Abstract

Coronary artery disease (CAD) is the most common cardiovascular disease (CVD), and previous studies have shown a significant association between N-glycosylation, a highly regulated posttranslational modification, and the development of atherosclerotic plaques. Our aim was to determine whether the N-glycome of immunoglobulin G (IgG) is associated with CAD, as N-glycans are known to alter the effector functions of IgG, which may enhance the inflammatory response in CAD. Therefore, in this study, we isolated IgG from subjects with coronary atherosclerosis (CAD+) and from subjects with clean coronaries (CAD−). The purified IgGs were denatured and enzymatically deglycosylated, and the released and fluorescently labelled N-glycans were analysed by ultra-high performance liquid chromatography based on hydrophilic interactions with fluorescence detection (HILIC-UHPLC-FLR). Sex-stratified analysis of 316 CAD− and 156 CAD+ cases revealed differences in IgG N-glycome composition. The most notable differences were observed in women, where the presence of sialylated N-glycan structures was negatively associated with CAD. The obtained chromatograms provide insight into the IgG N-glycome composition in CAD as well as the biomarker potential of IgG N-glycans in CAD. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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Review

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27 pages, 2833 KiB

Open AccessReview

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

by Chiranjeevi Pasala, Sahil Sharma, Tanaya Roychowdhury, Elisabetta Moroni, Giorgio Colombo and Gabriela Chiosis

Biomolecules 2024, 14(3), 282; https://doi.org/10.3390/biom14030282 - 27 Feb 2024

Viewed by 2609

Abstract

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes—namely, protein assemblies—under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation’s influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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12 pages, 1613 KiB

Open AccessReview

Red Blood Cells Oligosaccharides as Targets for Plasmodium Invasion

by Patrycja Burzyńska, Marlena Jodłowska, Agata Zerka, Jan Czujkowski and Ewa Jaśkiewicz

Biomolecules 2022, 12(11), 1669; https://doi.org/10.3390/biom12111669 - 11 Nov 2022

Cited by 1 | Viewed by 2172

Abstract

The key element in developing a successful malaria treatment is a good understanding of molecular mechanisms engaged in human host infection. It is assumed that oligosaccharides play a significant role in Plasmodium parasites binding to RBCs at different steps of host infection. The formation of a tight junction between EBL merozoite ligands and glycophorin receptors is the crucial interaction in ensuring merozoite entry into RBCs. It was proposed that sialic acid residues of O/N-linked glycans form clusters on a human glycophorins polypeptide chain, which facilitates the binding. Therefore, specific carbohydrate drugs have been suggested as possible malaria treatments. It was shown that the sugar moieties of N-acetylneuraminyl-N-acetate-lactosamine and 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA), which is its structural analog, can inhibit P. falciparum EBA-175-GPA interaction. Moreover, heparin-like molecules might be used as antimalarial drugs with some modifications to overcome their anticoagulant properties. Assuming that the principal interactions of Plasmodium merozoites and host cells are mediated by carbohydrates or glycan moieties, glycobiology-based approaches may lead to new malaria therapeutic targets. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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