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Special Issue "Functional Roles of Protein O-Glycosylation"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: 15 September 2018

Special Issue Editors

Guest Editor
Prof. Dr. Franz-Georg Hanisch

Institute of Biochemistry II, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Köln, Germany
Website | E-Mail
Interests: mucin-type O-glycosylation; O-glycoproteins; mucins; MUC1; cancer; innate immunity; galactosemia; glycomics; (glyco)proteomics; mass spectrometry
Guest Editor
Dr. Isabelle Breloy

University of Applied Sciences Bonn-Rhein-Sieg, Department Natural Sciences, D-53359 Rheinbach, Germany
Website | E-Mail
Interests: glycoanalysis; O-mannosylation; O-glycans; LacdiNac; proteomics; glycomics

Special Issue Information

Dear Colleagues,

Complex glycosylation of proteins comprizing O- and N-linked glycan chains represents a high-impact topic in current biological research and, in particular, in human life sciences. In this Special Issue, we undertake the attempt to collect contributions that cover at least part of this huge and still-growing field by restriction to the functional roles of protein O-glycosylation. No focus on a particular subtype is envisaged, e.g., the abundant mucin-type forms (O-GalNAc) or the more rare types of O-glycosylation, such as O-Man, O-Fuc, or O-Glc. Mucin-type O-glycans on mucins or mucin-like glycoproteins express ABH and Lewis blood group antigens on epithelia with impact in cancer diagnosis or as entry targets in microbial infection. Functional aspects of other types of O-glycosylation were revealed in congenital disorders of glycosylation (dystro glycanopathies) and in epithelial cell adhesion mediated by E-cadherin (O-Man). In addition to the well established involvement of O-Fuc glycosylation in notch signaling, the terminal LacdiNAc modification of extracellular matrix glycoproteins might play roles in the regulatory control of stem cell renewal.  

Prof. Dr. Franz-Georg Hanisch
Dr. Isabelle Breloy
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • O-glycosylation
  • membrane organization
  • cellular trafficking
  • cell-cell binding
  • cell-matrix binding
  • innate immunity
  • immunology
  • cancer

Published Papers (3 papers)

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Research

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Open AccessCommunication Structural Divergence in O-GlcNAc Glycans Displayed on Epidermal Growth Factor-like Repeats of Mammalian Notch1
Molecules 2018, 23(7), 1745; https://doi.org/10.3390/molecules23071745
Received: 20 June 2018 / Revised: 12 July 2018 / Accepted: 14 July 2018 / Published: 17 July 2018
PDF Full-text (3639 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Extracellular O-GlcNAc is a novel class of modification catalyzed by epidermal growth factor-like (EGF)-domain specific O-GlcNAc transferase (EOGT). In mammals, EOGT is required for ligand-mediated Notch signaling for vascular development. Previous studies have revealed that O-GlcNAc in mammalian cultured cells
[...] Read more.
Extracellular O-GlcNAc is a novel class of modification catalyzed by epidermal growth factor-like (EGF)-domain specific O-GlcNAc transferase (EOGT). In mammals, EOGT is required for ligand-mediated Notch signaling for vascular development. Previous studies have revealed that O-GlcNAc in mammalian cultured cells is subject to subsequent glycosylation, which may impose additional layers of regulation. This study aimed to analyze the O-GlcNAc glycans of Drosophila EGF20 as model substrates and mouse Notch1 EGF repeats by mass-spectrometry. The analysis of Drosophila EGF20 expressed in HEK293T cells revealed that the majority of the proteins are modified with an elongated form of O-GlcNAc glycan comprising terminal galactose or sialic acid residues. In contrast, recombinant Notch1 EGF repeats isolated from HEK293T cells revealed structural divergence of O-GlcNAc glycans among the different EGF domains. Although the majority of Notch1 EGF2 and EGF20 domains contained the extended forms of the glycan, the O-GlcNAc in many other domains mostly existed as a monosaccharide irrespective of the exogenous EOGT expression. Our results raised a hypothesis that an array of O-GlcNAc monosaccharides may impact the structure and function of Notch receptors. Full article
(This article belongs to the Special Issue Functional Roles of Protein O-Glycosylation)
Figures

Figure 1

Open AccessArticle O-Linked N-Acetylglucosamine Transiently Elevates in HeLa Cells during Mitosis
Molecules 2018, 23(6), 1275; https://doi.org/10.3390/molecules23061275
Received: 27 April 2018 / Revised: 19 May 2018 / Accepted: 24 May 2018 / Published: 26 May 2018
PDF Full-text (2738 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc modification influences many cellular mechanisms, including carbohydrate metabolism, signal transduction and protein degradation. Multiple studies also showed that cell
[...] Read more.
O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc modification influences many cellular mechanisms, including carbohydrate metabolism, signal transduction and protein degradation. Multiple studies also showed that cell cycle might be modulated by O-GlcNAc. Although the role of O-GlcNAc in the regulation of some cell cycle processes such as mitotic spindle organization or histone phosphorylation is well established, the general behaviour of O-GlcNAc regulation during cell cycle is still controversial. In this study, we analysed the dynamic changes of overall O-GlcNAc levels in HeLa cells using double thymidine block. O-GlcNAc levels in G1, S, G2 and M phase were measured. We observed that O-GlcNAc levels are significantly increased during mitosis in comparison to the other cell cycle phases. However, this change could only be detected when mitotic cells were enriched by harvesting round shaped cells from the G2/M fraction of the synchronized cells. Our data verify that O-GlcNAc is elevated during mitosis, but also emphasize that O-GlcNAc levels can significantly change in a short period of time. Thus, selection and collection of cells at specific cell-cycle checkpoints is a challenging, but necessary requirement for O-GlcNAc studies. Full article
(This article belongs to the Special Issue Functional Roles of Protein O-Glycosylation)
Figures

Figure 1

Review

Jump to: Research

Open AccessReview O-GlcNAc Code’ Mediated Biological Functions of Downstream Proteins
Molecules 2018, 23(8), 1967; https://doi.org/10.3390/molecules23081967
Received: 17 July 2018 / Revised: 31 July 2018 / Accepted: 4 August 2018 / Published: 6 August 2018
PDF Full-text (1827 KB) | HTML Full-text | XML Full-text
Abstract
As one of the post-translational modifications, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) often occurs on serine (Ser) and threonine (Thr) residues of specific substrate cellular proteins via the addition of O-GlcNAc group by O-GlcNAc transferase
[...] Read more.
As one of the post-translational modifications, O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) often occurs on serine (Ser) and threonine (Thr) residues of specific substrate cellular proteins via the addition of O-GlcNAc group by O-GlcNAc transferase (OGT). Maintenance of normal intracellular levels of O-GlcNAcylation is controlled by OGT and glycoside hydrolase O-GlcNAcase (OGA). Unbalanced O-GlcNAcylation levels have been involved in many diseases, including diabetes, cancer, and neurodegenerative disease. Recent research data reveal that O-GlcNAcylation at histones or non-histone proteins may provide recognition platforms for subsequent protein recruitment and further initiate intracellular biological processes. Here, we review the current understanding of the ‘O-GlcNAc code’ mediated intracellular biological functions of downstream proteins. Full article
(This article belongs to the Special Issue Functional Roles of Protein O-Glycosylation)
Figures

Graphical abstract

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: O-GlcNAc code’ mediated biological functions of downstream proteins
Author: Jingji Jin
Affiliation: School of Life Sciences, Jilin University, Changchun, Jilin, China; jjjin@jlu.edu.cn
Abstract: As one of the post-translational modifications, O-GlcNAc (O-linked b-N-acetylglucosamine) modification (O-GlcNAcylation) often occurs on serine (Ser) and threonine (Thr) residues of the specific substrate cellular proteins via the addition of O-GlcNAc group by O-GlcNAc transferase (OGT). It has been known that abnormal O-GlcNAcylation has been implicated in many human diseases including diabetes, cancer, and neurodegenerative disease. Recent research data reveal that O-GlcNAcylation at histones or non-histone proteins may provide recognition platforms for subsequent protein recruitment and further initiate intracellular biological processes. Here, we review the current understanding of the ‘O-GlcNAc code’ mediated intracellular biological functions of downstream proteins.

Title: The many ways by which the single O-GlcNAc glycosylation may orchestrate the diversity of complex glycosylations
Author: Tony Lefebvre
Affiliation: University Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, 59000 Lille, France; tony.lefebvre@univ-lille1.fr
Abstract: Unlike complex glycosylations, O-GlcNAcylation consists in the addition of a unique residue of N-acetylglucosamine to serine and threonine of target proteins and is confined within the nucleocytoplasmic and mitochondrial compartments. Nevertheless, a number of clues tend to show that O-GlcNAcylation is a pivotal regulatory element of its complex counterparts. In this perspective, we first gather the evidence reported to date regarding this connection. Next, we propose different levels of regulation that encompass the control of the wide class of glycosylation enzymes via their expression, catalytic activity and subcellular localization. Lastly, we ought to better envision that nutrient fluxes control glycans elaboration not only at the level of their structure composition but also through sweet regulating actors.

Title: O-linked N-acetylglucosamine (O-GlcNAc) transiently elevates in HeLa cells during mitosis
Author: Tamás Nagy
Affiliation: Department of Laboratory Medicine, University of Pécs, Pécs, Hungary
Email:
Abstract: O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification of serine and threonine residues on nuclear and cytoplasmic proteins. O-GlcNAc modification influences many cellular mechanisms, including carbohydrate metabolism, signal transduction and protein degradation. Multiple studies also showed that cell cycle might be also modulated by O-GlcNAc. Although the role of O-GlcNAc in the regulation of some cell cycle processes such as mitotic spindle organization or histone phosphorylation is well established, the general behaviour of O-GlcNAc regulation during cell cycle is still controversial. In this study, we analysed the dynamic changes of overall O-GlcNAc levels in HeLa cells using double thymidine block. O-GlcNAc levels in G1, S, G2 and M phase were measured. We observed that O-GlcNAc levels are significantly increased during mitosis in comparison to the other cell cycle phases. However, this change could only be detected when mitotic cells were also enriched by harvesting round shaped cells from the G2/M fraction of the synchronized cells. Our data verify that O-GlcNAc is elevated during mitosis, but also emphasizes that O-GlcNAc levels can significantly change in a short period of time. Thus, optimal selection of any given population of cells at crucial cell-cycle checkpoints is a challenging, but necessary requirement for O-GlcNAc studies.

Title: Differential glycosylation structures of extracellular O-GlcNAc displayed on mammalian Notch1 EGF repeats
Author: Tetsuya Okajima
Affiliation: Department of Biochemistry II, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan
Email:
Abstract: Extracellular O-GlcNAc is a new class of modification that is catalyzed by epidermal growth factor-like (EGF)-domain specific O-GlcNAc transferase (EOGT). In mammals, EOGT is required for ligand-mediated Notch signaling during vascular development. Previous studies revealed that O-GlcNAc in mammalian cultured cells is subject to subsequent glycosylation that may impose additional layers of regulation. In this study, we analyzed O-GlcNAc glycans on Drosophila EGF20 as a model substrate and mouse Notch1 EGF repeats by mass-spectrometry. The analysis of Drosophila EGF20 expressed in HEK293T cells revealed that nearly all of O-GlcNAc glycans have elongated structures with terminal galactose or sialic acid residues. In contrast, Notch1 EGF repeats isolated from HEK293T cells turned out to have differential O-GlcNAcylation structures on respective domains comprising EGF repeats. Although Notch1 EGF2 contained the extended structure, many other domains involved in ligand-interaction are resistant to glycan elongation irrespective of exogenous EOGT expression. These results suggest that O-GlcNAc monosaccharides may regulate Notch1 function.

Title: Multicellular human gastric cancer spheroids mimic the glycosylation phenotype of patients’ tumours
Author: Celso A. Reis
Affiliation: Medical Faculty, University of Porto, Porto, Portugal
Email:
Abstract: Cellular glycosylation plays a pivotal role in several molecular functions such as cell–cell recognition, communication, and adhesion. Aberrant glycosylation significantly contributes to the acquisition of malignant features in tumour progression. To mimic the in vivo features, an innovative 3D high-throughput cell culture methodology has been developed for gastric cancer cells. Image analysis were applied to determine spheroid’s physical characteristics such as size, morphology and solidity as well as to assess the impact of glycosylation inhibitors in the spheroid formation. Detailed analysis of key glycans and glycoproteins displayed by the spheroids and their counterpart cells cultured in conventional 2D conditions was performed. Altogether, our results show that by applying 3D cell culture methods, the cell glycocalix undergoes changes, displaying increased expression of cancer associated glycan antigens and ultimately, simulating better the glycosylation phenotype of the tumour.

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