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Updated: Oct 17, 2026

Identification and Characterization of Protein Glycosylation using Specific Endo- and Exoglycosidases
Published on: December 26, 2011
Proximity-Induced Protein Deglycosylation by Endogenous O-GlcNAcase
Haixing Xu1, Bowen Ma1, Yunpeng Huang1
1Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, China.
Abstract:
O-GlcNAcylation is an important post-translational modification that regulates numerous cellular processes, yet tools enabling selective removal of O-GlcNAc from individual proteins via endogenous O-GlcNAcase (OGA) in living cells remain limited. Here, we report De-O-GlcNAcylation-targeting chimeras (DOGTACs), a chemically induced proximity strategy that selectively reduces O-GlcNAc from target proteins by recruiting endogenous OGA. Initial designs incorporating potent competitive OGA inhibitors efficiently engaged OGA but failed to induce de-O-GlcNAcylation, revealing that catalytic competence is essential for productive proximity-driven editing. By attenuating inhibitor potency while retaining OGA engagement, we developed optimized DOGTACs that promote concentration- and time-dependent, target-specific de-O-GlcNAcylation in living cells without perturbing global O-GlcNAc levels. Furthermore, we successfully applied DOGTAC to additional target proteins including FKBP12F36V fused proteins and endogenous CK2α across different cell lines. Besides, we found DOGTAC (R)-C4 treatment could reduce the stability of FKBP12F36V fused-NUP98-KDM5A in cells. Collectively, this work established attenuated competitive inhibitors as recruitment modules for catalytic enzyme engagement and a novel strategy, DOGTAC, for targeted de-O-GlcNAcylation via endogenous OGA recruitment in living cells.
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