O-GlcNAcylation reduces proteome solubility and regulates the formation of biomolecular condensates in human cells

Senhan Xu, Kejun Yin, Xing Xu, Longping Fu and Ronghu Wu ()
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Senhan Xu: Georgia Institute of Technology
Kejun Yin: Georgia Institute of Technology
Xing Xu: Georgia Institute of Technology
Longping Fu: Georgia Institute of Technology
Ronghu Wu: Georgia Institute of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract O-GlcNAcylation plays critical roles in the regulation of protein functions and cellular activities, including protein interactions with other macromolecules. While the formation of biomolecular condensates (or biocondensates) regulated by O-GlcNAcylation in a few individual proteins has been reported, systematic investigation of O-GlcNAcylation on the regulation of biocondensate formation remains to be explored. Here we systematically study the roles of O-GlcNAcylation in regulating protein solubility and its impacts on RNA-protein condensates using mass spectrometry-based chemoproteomics. Unexpectedly, we observe a system-wide decrease in the solubility of proteins modified by O-GlcNAcylation, with glycoproteins involved in focal adhesion and actin binding exhibiting the most significant decrease. Furthermore, O-GlcNAcylation sites located in disordered regions and with fewer acidic and aromatic residues nearby are related to a greater drop in protein solubility. Additionally, we discover that a specific group of O-GlcNAcylation events promotes the dissociation of RNA-protein condensates under heat stress, while some enhance the formation of RNA-protein condensates during the recovery phase. Using site mutagenesis, inhibition of O-GlcNAc transferase, and fluorescence microscopy, we validate that O-GlcNAcylation regulates the formation of biocondensates for YTHDF3 and NUFIP2. This work advances our understanding of the functions of protein O-GlcNAcylation and its roles in the formation of biomolecular condensates.

Date: 2025
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DOI: 10.1038/s41467-025-59371-4

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