The Mouse N-Glycoproteome Atlas: Tissue-Specific Glycan Signatures Decoded
Glycosylation is one of the most complex post-translational modifications of proteins. Minute structural differences in a single N-glycan chain can directly determine a protein's fate within the body, its half-life, and even its functional output. However, due to the high degree of structural microheterogeneity and non-linear complexity inherent to glycan chains, the scientific community has long lacked a high-resolution, site-specific glycoproteome atlas that spans multiple tissues across the entire organism.
In January 2026, the research team led by Sun from Northwest University published their latest findings in Nature Communications in an article titled "A comprehensive N-glycoproteome atlas reveals tissue-specific glycan remodeling but non-random structural microheterogeneities." Utilizing their independently developed software, StrucGP, the study systematically mapped the N-glycoproteome across 24 distinct mouse tissues—comprising 16 major organs, 7 brain regions, and serum—thereby providing an unprecedented, systematic perspective on how glycosylation regulates tissue function.
The research team collected 24 types of tissue samples from five male and five female C57BL/6N mice. They enriched glycopeptides using a combination of hydrophilic interaction chromatography (HILIC) and mixed-mode anion exchange chromatography, followed by mass spectrometry analysis utilizing a stepped high-energy collision dissociation (HCD) strategy.
Fig. 1 Study design and analytical workflow of the mouse multi-tissue N-glycoproteome atlas. (Wu, et al. 2026)
The final dataset comprises:
Notably, 88.2% of the identified glycan structures met high-confidence criteria (probability ≥ 0.82), as determined by an integrated confidence assessment framework. This dataset covers 63.5% of the mouse N-glycoproteins currently annotated in UniProtKB, while also identifying 2,795 glycoproteins that had not been previously annotated.
The study revealed significant differences in the glycan landscapes across various tissues—differences so distinct that their discriminatory power in distinguishing between tissues surpassed even that of proteomic and glycomic data.
These tissue-specific glycan patterns correlated strongly with the expression profiles of Glycosyltransferases. For instance, the high expression of the Mgat3 gene in neural tissues corresponded directly to the enrichment of bisecting core structures; similarly, the high expression of Fut9 in the kidney and brain regions explained the significant increase in Fucosylated Glycan Structures.
The study further tracked 62 conserved glycoproteins that are ubiquitously expressed across multiple tissue types. The results demonstrated that, despite possessing identical protein backbone sequences, the N-Glycan Structures attached to these proteins underwent significant remodeling depending on the specific tissue type.
Take the Mannose-6-phosphate receptor (M6pr) as an example: at the Asn-84 glycosylation site, the liver predominantly featured highly sialylated, complex-type glycan structures—a profile consistent with the liver's functional requirements for protein longevity (extended half-life) and endosomal recycling. In contrast, in the seminal vesicle and pancreas, Asn-84 was mainly decorated with hybrid-type glycans, but sialylation was largely absent in the seminal vesicle. This site-specific remodeling of glycan chains indicates that glycosylation serves as a crucial mechanism through which cells finely tune protein function in response to local physiological demands. In contrast, the Asn-914 site of the cell-surface hyaluronidase (Cemip2) maintains a highly conserved glycan composition across various tissues, suggesting that the functional integrity of certain glycosylation sites imposes strict requirements on structural stability.
The subcellular localization of a glycoprotein is one of the key factors determining the structure of its associated glycans.
This finding reveals a distinct gradient in glycan structure, transitioning from a state of high conservation within the intracellular environment to one of high diversity in the extracellular environment.
To investigate the phenomenon of multiple distinct glycan structures coexisting at a single glycosylation site, this study constructed glycan co-occurrence networks. The results revealed that site-specific microheterogeneity is not a random occurrence but rather adheres to distinct modular principles.
The multi-tissue N-glycoproteome atlas of the mouse, established by this study, provides a fundamental resource of significant importance for glycobiology research and translational medicine.
The research team also notes that significant differences exist between mouse and human glycosylation (e.g., mice express Neu5Gc and α-Gal epitopes, whereas humans do not); therefore, cross-species comparative studies are critical for translational applications.
Through a site-specific structural characterization strategy, this study expands the scope of glycobiology from single organs to a multi-tissue systemic level, and—for the first time at a proteome-wide scale—reveals the non-random patterns governing glycan microheterogeneity. With the further advancement of single-cell and spatial glycoproteomics technologies, this atlas will serve as a crucial cornerstone for decoding the biological functions of glycosylation.
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