Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases
Abstract
Glycosylation encompasses a broad spectrum of post-translational modifications (PTMs) that shape protein stability, spatial organization, and function. Traditionally, it is classified into two major categories: complex glycosylation within the secretory pathway - including N-glycosylation, mucin-type O-glycosylation, glycosaminoglycans (GAGs), and glycolipids - which generate structurally stable and long-lived modifications; and O-GlcNAcylation, a highly dynamic modification of nucleocytoplasmic and mitochondrial proteins that rapidly responds to metabolic and environmental cues. While this dichotomous framework has guided our understanding of glycan biology, emerging evidence now reveals that glycosylations are functionally interconnected through shared metabolic substrates, and regulatory circuits. Here, we revisit this classical classification and integrate it into a modern, systems-level view of glycosylation. We highlight the nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc) as a metabolic node reflecting cellular nutrient status and fuelling both complex glycan synthesis and O-GlcNAcylation. UDP-GlcNAc pool fluctuations drive coordinated remodeling across glycosylation pathways, and dysregulation of this hub is associated with diverse human diseases. We discuss how O-GlcNAcylation functions as a supplementary regulatory PTM, modulating glycosylation-related enzymes and proteins through both direct effects on their interactions, stability, localisation and activity, and via broader transcriptional and epigenetic programs, thereby dynamically controlling otherwise stable glycosylation processes. Examples from metabolic, cardiovascular, neurological diseases, cancer and congenital disorders of glycosylation (CDGs) illustrate how perturbations in one glycosylation pathway propagate through the glycosylation network, reshaping cellular identity and disease trajectories. We support a paradigm in which glycosylation operates as an integrated regulatory framework linking metabolism, signaling, and extracellular architecture, providing new perspectives for disease stratification and therapeutic intervention.
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BibTeX
@article{very2026crosstalk,
title = {{Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases}},
author = {Ninon Very and Ikram El Yazidi-Belkoura},
journal = {Molecular metabolism},
year = {2026},
month = jun,
doi = {10.1016/j.molmet.2026.102400},
url = {https://hal.science/hal-05736171v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases
AU - Ninon Very
AU - Ikram El Yazidi-Belkoura
PY - 2026
DA - 2026/06/13
JO - Molecular metabolism
DO - 10.1016/j.molmet.2026.102400
UR - https://hal.science/hal-05736171v1
AB - Glycosylation encompasses a broad spectrum of post-translational modifications (PTMs) that shape protein stability, spatial organization, and function. Traditionally, it is classified into two major categories: complex glycosylation within the secretory pathway - including N-glycosylation, mucin-type O-glycosylation, glycosaminoglycans (GAGs), and glycolipids - which generate structurally stable and long-lived modifications; and O-GlcNAcylation, a highly dynamic modification of nucleocytoplasmic and mitochondrial proteins that rapidly responds to metabolic and environmental cues. While this dichotomous framework has guided our understanding of glycan biology, emerging evidence now reveals that glycosylations are functionally interconnected through shared metabolic substrates, and regulatory circuits. Here, we revisit this classical classification and integrate it into a modern, systems-level view of glycosylation. We highlight the nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc) as a metabolic node reflecting cellular nutrient status and fuelling both complex glycan synthesis and O-GlcNAcylation. UDP-GlcNAc pool fluctuations drive coordinated remodeling across glycosylation pathways, and dysregulation of this hub is associated with diverse human diseases. We discuss how O-GlcNAcylation functions as a supplementary regulatory PTM, modulating glycosylation-related enzymes and proteins through both direct effects on their interactions, stability, localisation and activity, and via broader transcriptional and epigenetic programs, thereby dynamically controlling otherwise stable glycosylation processes. Examples from metabolic, cardiovascular, neurological diseases, cancer and congenital disorders of glycosylation (CDGs) illustrate how perturbations in one glycosylation pathway propagate through the glycosylation network, reshaping cellular identity and disease trajectories. We support a paradigm in which glycosylation operates as an integrated regulatory framework linking metabolism, signaling, and extracellular architecture, providing new perspectives for disease stratification and therapeutic intervention.
SN - 2212-8778
ER -