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bioRxiv · 10.64898/2025.12.11.693745

Mucin-type O-glycans regulate proteoglycan stability and chondrocyte maturation

Dong, X.·Bedillion, S.·Gosnell, K. E.·Zhao, P.·Basu, A.·Suryadevara, K.·Chapla, D.·Wells, L.·Weiss, R. J.
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Abstract

O-glycosylation is a ubiquitous post-translational modification essential for protein stability, cell signaling, and tissue organization, yet how distinct O-glycan subclasses coordinate tissue development remains unclear. Here, we identify functional crosstalk between extended mucin-type O-glycans and heparan sulfate proteoglycans (HSPGs). Genetic ablation of {beta}-1,3-galactosyltransferase 1 (C1GALT1) or its chaperone COSMC in human chondrocytes reduced cell surface HSPGs and fibroblast growth factor (FGF) binding, leading to impaired MAPK/ERK signaling, which was recapitulated in hypomorphic COSMC-CDG patient cells. Transcriptomic and secretome analyses revealed selective loss of proteoglycan expression and broader extracellular matrix remodeling in COSMC- and C1GALT1-deficient cells. Mechanistically, truncation of O-GalNAc glycans reduced Syndecan-1 levels at the cell surface via enhancing its lysosome-dependent degradation and diminished CD44v3-mediated FGF1 binding. Functionally, loss of complex O-GalNAc glycans disrupted chondrogenesis of growth plate-like chondroprogenitors. Overall, these findings reveal previously unrecognized roles for mucin-type O-glycans in maintaining proteoglycan stability and function, highlighting cross-regulatory mechanisms of glycosylation crucial for normal development that likely contribute to the pathophysiology of glycosylation-related disorders.

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Dong, X., Bedillion, S., Gosnell, K. E., Zhao, P., Basu, A., Suryadevara, K., Chapla, D., Wells, L., Weiss, R. J.. 2025-12-13. Mucin-type O-glycans regulate proteoglycan stability and chondrocyte maturation. https://doi.org/10.64898/2025.12.11.693745

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