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Functional glycoproteomics by integrated network assembly and partitioning

Griffin, M. E.; Thompson, J. W.; Xiao, Y.; Sweredoski, M. J.; Jensen, E. H.; Koldobskaya, Y.; Schacht, A. L.; Kim, T. D.; Choudhry, P.; Lomenick, B.; Garbis, S. D.; Moradian, A.; Hsieh-Wilson, L. C.

2023-06-14 cell biology
10.1101/2023.06.13.541482 bioRxiv
Show abstract

The post-translational modification (PTM) of proteins by O-linked {beta}-N-acetyl-D-glucosamine (O-GlcNAcylation) is widespread across the proteome during the lifespan of all multicellular organisms. However, nearly all functional studies have focused on individual protein modifications, overlooking the multitude of simultaneous O-GlcNAcylation events that work together to coordinate cellular activities. Here, we describe Networking of Interactors and SubstratEs (NISE), a novel, systems-level approach to rapidly and comprehensively monitor O-GlcNAcylation across the proteome. Our method integrates affinity purification-mass spectrometry (AP-MS) and site-specific chemoproteomic technologies with network generation and unsupervised partitioning to connect potential upstream regulators with downstream targets of O-GlcNAcylation. The resulting network provides a data-rich framework that reveals both conserved activities of O-GlcNAcylation such as epigenetic regulation as well as tissue-specific functions like synaptic morphology. Beyond O-GlcNAc, this holistic and unbiased systems-level approach provides a broadly applicable framework to study PTMs and discover their diverse roles in specific cell types and biological states.

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