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New Research Perspectives in Protein Glycosylation
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New Research Perspectives in Protein Glycosylation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 25 December 2026 | Viewed by 5863

Editor

Dr. Hirokazu Yagi

E-Mail Website
Guest Editor
Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan
Interests: glycan analysis; glycan function; glycoproteomics; glycosylation systems

Special Issue Information

Dear Colleagues,

Protein glycosylation is a fundamental and highly dynamic post-translational modification that regulates diverse biological processes, including protein folding, stability, intracellular trafficking, and intercellular communication. Recent advances in analytical techniques, glycoengineering, and systems biology have uncovered unexpected complexity and plasticity in glycosylation patterns across species, tissues, and developmental or physiological states. This Special Issue will present new perspectives on the mechanisms, functions, and evolutionary diversity of protein glycosylation. We welcome contributions on emerging glycosylation pathways, atypical or context-dependent glycan structures, glycan-related diseases, and the role of glycosylation in immunity, signaling, and homeostasis. Studies on state-of-the-art methodologies, such as live-cell glycoprotein imaging, glycoproteomics, multi-omics integration, and computational modeling, are particularly encouraged. By integrating insights from molecular biology, structural biology, and biotechnology, this Special Issue will expand our understanding of how the glycosylation landscape is dynamically regulated and how it shapes protein function and organismal physiology.

Dr. Hirokazu Yagi
Guest Editor

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 submissions that pass pre-check are 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 250 words) can be sent to the Editorial Office for assessment.

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Keywords

  • glycan function
  • glycan structural analysis
  • glycoproteomics
  • glycoengineering
  • systems glycobiology

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Published Papers (5 papers)

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Research

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15 pages, 2010 KB  
Article
N- and O-glycans in Unfertilized Chum Salmon (Oncorhynchus keta) Eggs Using Glycomic Techniques
by Masaki Kurogochi, Kai Suzuki, Di Wu, Hisatoshi Hanamatsu, Ken Kitajima, Chihiro Sato and Jun-ichi Furukawa
Int. J. Mol. Sci. 2026, 27(10), 4646; https://doi.org/10.3390/ijms27104646 - 21 May 2026
Viewed by 423
Abstract
Genomic analysis of various fish has advanced in recent years; however, predicting glycan information from the genomic data alone remains challenging. Glycomic techniques have therefore attracted considerable attention. In this study, we analyzed N- and O-glycans in unfertilized Oncorhynchus keta eggs [...] Read more.
Genomic analysis of various fish has advanced in recent years; however, predicting glycan information from the genomic data alone remains challenging. Glycomic techniques have therefore attracted considerable attention. In this study, we analyzed N- and O-glycans in unfertilized Oncorhynchus keta eggs using glycomic techniques, such as a glycoblotting procedure, a sialic acid linkage-specific alkylamidation, and an evaporative β-elimination with pyrazolone. N-Glycomic analysis revealed that biantennary N-glycans were predominant, and that sialylation occurred via an α2,3 linkage. In addition, numerous sulfated N-glycans were observed, some of which had not been reported previously. Tandem mass spectrometry analyses indicated that most of the sulfate groups were attached to GlcNAc linked to mannose within the core structure. The sulfation sites of the unknown sulfated glycans were the same; however, a GlcNAc residue was lost from the core structure. In O-glycomics, oligo-sialylated O-glycans, which contain between one to seven sialic acid residues, were observed in the unfertilized eggs. Most of the sialic acids in the O-glycans were Neu5Gc, and there was no α2,3 linkage. Full article
(This article belongs to the Special Issue New Research Perspectives in Protein Glycosylation)
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13 pages, 1889 KB  
Article
Structural Characterization of Glycoprotein Glycans and Glycosaminoglycans of Brain Tissues in Slc35a3-Knockout Mice
by Ikumi Hirose, Hisatoshi Hanamatsu, Shuji Mizumoto, Rina Yamashita, Shuhei Yamada, Jun-ichi Furukawa, Tatsuya Furuichi and Hirokazu Yagi
Int. J. Mol. Sci. 2026, 27(4), 1643; https://doi.org/10.3390/ijms27041643 - 8 Feb 2026
Viewed by 1112
Abstract
Glycosylation depends on luminal nucleotide sugars delivered by solute carrier 35 (SLC35) transporters. SLC35A3 is a uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In humans, biallelic mutations in SLC35A3 cause arthrogryposis, mental retardation, and seizures (AMRS). To define how loss of SLC35A3 function reshapes [...] Read more.
Glycosylation depends on luminal nucleotide sugars delivered by solute carrier 35 (SLC35) transporters. SLC35A3 is a uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In humans, biallelic mutations in SLC35A3 cause arthrogryposis, mental retardation, and seizures (AMRS). To define how loss of SLC35A3 function reshapes the neural glycome, we profiled N-, O-, and glycosaminoglycans (GAGs) in Slc35a3 knockout mouse brains. N- and O-glycans were analyzed by MALDI-TOF MS, and GAG disaccharides were quantified by anion-exchange HPLC. Knockout mouse brains exhibited attenuation of complex-type N-glycans with a reciprocal rise in high-mannose species, as revealed by MALDI-TOF MS profiling. In contrast, ConA lectin blotting showed no significant change, consistent with its preferential detection of mannose-rich glycans. Branching analysis revealed loss of tri- and tetra-antennary structures compared with biantennary species. O-glycan profiling showed core-2-type species (Hex2HexNAc2 backbone) decreased. The dominant disialyl core-1 remained stable. Total GAG output (chondroitin/dermatan sulfate, heparan sulfate, and hyaluronan) was preserved. These findings support a microdomain model in which SLC35A3 acts as a locally effective supplier of UDP-GlcNAc to MGAT4 (branching N-acetylglucosaminyltransferase that installs the β1,4-GlcNAc arm) in the brain, while alternative routes buffer UDP-GlcNAc delivery for GAG and mucin-type O-glycan biosynthesis. Accordingly, AMRS may be attributed to impaired higher-order N-glycan branching in the brain. Full article
(This article belongs to the Special Issue New Research Perspectives in Protein Glycosylation)
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Review

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36 pages, 2104 KB  
Review
Distinct O-Linked Glycosylation Systems in Signaling and Immune Regulation
by Shuguang Wang, Shibo Xiao, Yuman Huang and Xianwang Wang
Int. J. Mol. Sci. 2026, 27(11), 5119; https://doi.org/10.3390/ijms27115119 - 5 Jun 2026
Viewed by 546
Abstract
O-linked glycosylation comprises distinct regulatory systems, including secretory-pathway mucin-type O-GalNAc glycosylation and intracellular O-GlcNAcylation. These modifications both target serine/threonine residues but differ in glycan structure, cellular compartment, enzymatic machinery, and biological function. This narrative review was based on targeted searches of PubMed, Web [...] Read more.
O-linked glycosylation comprises distinct regulatory systems, including secretory-pathway mucin-type O-GalNAc glycosylation and intracellular O-GlcNAcylation. These modifications both target serine/threonine residues but differ in glycan structure, cellular compartment, enzymatic machinery, and biological function. This narrative review was based on targeted searches of PubMed, Web of Science, and related literature using keywords related to O-glycosylation, O-GalNAc glycosylation, O-GlcNAcylation, immune regulation, cell signaling, glycoproteomics, and congenital disorders of glycosylation (CDG). We summarize evidence that mucin-type O-glycosylation regulates receptor behavior, cell adhesion, immune checkpoints, immunoglobulin function, antigen recognition, and pathogen–host interactions, whereas O-GlcNAcylation mainly modulates intracellular signaling, transcriptional control, stress responses, post-translational modification crosstalk, and innate immune pathways. We also discuss how glycosylation defects, including CDG and selected O-linked glycosylation disorders, connect genetic variation with disease phenotypes. Recent advances in site-specific glycoproteomics, O-glycoprotease-assisted workflows, LC–MS/MS-based glycopeptide analysis, and spatial or temporal profiling have improved mechanistic interpretation but still face limitations in site localization, structural resolution, and functional validation. Overall, the evidence supports the hypothesis that distinct O-linked glycosylation systems act through different molecular mechanisms but converge on signaling regulation, immune homeostasis, and disease susceptibility. Full article
(This article belongs to the Special Issue New Research Perspectives in Protein Glycosylation)
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26 pages, 3962 KB  
Review
Exploring Small-Molecule Inhibitors of Glucosidase II: Advances, Challenges, and Therapeutic Potential in Cancer and Viral Infection
by Tay Zar Myo Oo, Yupanun Wuttiin, Kanyamas Choocheep, Warunee Kumsaiyai, Piyawan Bunpo and Ratchada Cressey
Int. J. Mol. Sci. 2025, 26(24), 11867; https://doi.org/10.3390/ijms262411867 - 9 Dec 2025
Cited by 2 | Viewed by 1412
Abstract
Glucosidase II (GluII) is a heterodimeric enzyme localized in the endoplasmic reticulum (ER), essential for the sequential trimming of glucose residues during N-linked glycosylation. This critical function facilitates glycoprotein folding via the calnexin/calreticulin chaperone system, maintaining ER homeostasis. Dysregulation or inhibition of GluII [...] Read more.
Glucosidase II (GluII) is a heterodimeric enzyme localized in the endoplasmic reticulum (ER), essential for the sequential trimming of glucose residues during N-linked glycosylation. This critical function facilitates glycoprotein folding via the calnexin/calreticulin chaperone system, maintaining ER homeostasis. Dysregulation or inhibition of GluII has been implicated in various pathological processes, including cancer, viral infections, and glycoprotein misfolding disorders. This review summarizes the current knowledge of GluII’s structure and function, highlights a wide range of natural and synthetic GluII inhibitors—including iminosugar derivatives (e.g., deoxynojirimycin (DNJ), castanospermine (CAST)), non-iminosugar compounds (e.g., bromoconduritol, catechins), and mechanism-based cyclophellitol analogues—and evaluates their biological effects and therapeutic potential. The cellular impact of GluII inhibition is explored in the context of ER stress, unfolded protein response (UPR), tumor cell apoptosis, and viral replication. Key challenges in developing selective GluII inhibitors are discussed, with a focus on strategies to minimize off-target effects, including prodrug design, allosteric modulation, and emerging genetic approaches such as microRNA (miRNA)-mediated downregulation of GluII subunits. Taken together, these insights underscore the therapeutic relevance of GluII as a druggable target and pave the way for the rational design of next-generation inhibitors in oncology, infectious diseases, and metabolic disorders. Full article
(This article belongs to the Special Issue New Research Perspectives in Protein Glycosylation)
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17 pages, 5308 KB  
Review
Free GPIs and Comparison of GPI Structures Among Species
by Stella Amarachi Ihim and Morihisa Fujita
Int. J. Mol. Sci. 2025, 26(23), 11592; https://doi.org/10.3390/ijms262311592 - 29 Nov 2025
Viewed by 1427
Abstract
Glycosylphosphatidylinositols (GPIs) are complex glycolipids that function as membrane anchors for a wide array of eukaryotic proteins, collectively referred to as GPI-anchored proteins (GPI-APs). These structures are critical for various cellular processes including signal transduction, host–pathogen interactions, and immune evasion. While GPI-APs have [...] Read more.
Glycosylphosphatidylinositols (GPIs) are complex glycolipids that function as membrane anchors for a wide array of eukaryotic proteins, collectively referred to as GPI-anchored proteins (GPI-APs). These structures are critical for various cellular processes including signal transduction, host–pathogen interactions, and immune evasion. While GPI-APs have been extensively studied, increasing attention is being paid to non-protein-linked GPI, called free GPIs, which have been identified in both protozoan parasites and mammalian cells. In protozoa such as Trypanosoma brucei, Trypanosoma cruzi, Toxoplasma gondii, Plasmodium falciparum, and Leishmania spp., free GPIs play roles in virulence, immune modulation, and parasite survival. In mammals, free GPIs have been detected in several tissues and pathogenic conditions of paroxysmal nocturnal hemoglobinuria caused by PIGT mutation and rare blood group phenotypes. This review provides a comparative overview of the structure and biosynthesis of free GPIs and GPI-APs across species, highlighting unique adaptations in each. We also discuss the emerging physiological and pathological roles of free GPIs, proposing that these underexplored molecules may serve as important biomarkers and therapeutic targets. Understanding the diversity and function of free GPIs offers new insights into glycobiology and host–pathogen interactions. Full article
(This article belongs to the Special Issue New Research Perspectives in Protein Glycosylation)
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