Nuclear N-Glycosylation Redefines the Glycoscape and Directs Cell Identity

Glycans modify nucleic acids, proteins and lipids in fundamental biological processes, but have long been considered confined to the secretory pathway and cell surface. Here, we challenge this view with evidence that N-glycosylation, a ubiquitous glycan modification, occurs within cell nuclei across tissues and species, exhibiting cell type-dependent abundance and localization patterns. Using a multi-faceted approach, we show that numerous classical membrane and secreted glycoproteins localize to the nucleus with N-glycan modifications, exemplified by the cell adhesion molecule L1CAM. Mechanistically, we show that the N-glycosylated L1CAM is transported to the nucleus by KPNB1, where it transcriptionally modulates neuronal differentiation. Moreover, this nuclear N-glycosylation event contributes to neurodevelopmental disorders and is pharmacologically reversible. These findings revise the cellular geography of N-glycosylation and expand the known routes of protein trafficking, and highlight nuclear N-glycosylation pathways as potential therapeutic entry points for developmental disorders.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2025-12-19
DOI
https://doi.org/10.64898/2025.12.17.694357
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Nuclear N-Glycosylation Redefines the Glycoscape and Directs Cell Identity

Suyun Huang, X. G. Wu, Yan Zhang, Jiafeng Yang et al.
bioRxiv (Cold Spring Harbor Laboratory)
Glycosylation and Glycoproteins Research
article

Nuclear N-Glycosylation Redefines the Glycoscape and Directs Cell Identity

Suyun Huang, X. G. Wu, Yan Zhang, Jiafeng Yang, Fenjie Li, Jiaojiao Xi, Wei Zhong, Jixiao Zeng, Yuetong Sun, Kaining Chen, Xingui Wu, Xiaoyu Zuo, Yixuan Xie, Wenwen Li, Xingyu Liu, Chi Zhang, Li Yang, Haojie Lu, Qiang Wu, Benjamin A. Garcia, Huimin Xia, Xingqiang Lai, Jiazhang Chen, Yi Zheng, Wenhao Zhou
article en

Abstract

Glycans modify nucleic acids, proteins and lipids in fundamental biological processes, but have long been considered confined to the secretory pathway and cell surface. Here, we challenge this view with evidence that N-glycosylation, a ubiquitous glycan modification, occurs within cell nuclei across tissues and species, exhibiting cell type-dependent abundance and localization patterns. Using a multi-faceted approach, we show that numerous classical membrane and secreted glycoproteins localize to the nucleus with N-glycan modifications, exemplified by the cell adhesion molecule L1CAM. Mechanistically, we show that the N-glycosylated L1CAM is transported to the nucleus by KPNB1, where it transcriptionally modulates neuronal differentiation. Moreover, this nuclear N-glycosylation event contributes to neurodevelopmental disorders and is pharmacologically reversible. These findings revise the cellular geography of N-glycosylation and expand the known routes of protein trafficking, and highlight nuclear N-glycosylation pathways as potential therapeutic entry points for developmental disorders.

bioRxiv (Cold Spring Harbor Laboratory)
Shanghai Medical College of Fudan University (CN), Washington University in St. Louis (US), Shenzhen Maternity and Child Healthcare Hospital (CN), Guangzhou Women and Children Medical Center (CN), Maternal and Child Health Care Hospital of Bao'an (CN), Shenzhen Children's Hospital (CN), Guangzhou Medical University (CN)
Harvard University, Guangzhou Medical University, National Natural Science Foundation of China, Sun Yat-sen University, Fudan University, South China University of Technology, Guangdong Academy of Agricultural Sciences, Shanghai Medical College, Fudan University, Basic and Applied Basic Research Foundation of Guangdong Province
Openalex Percentile: Top 62%
Glycosylation and Glycoproteins Research
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