O-Linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of proteins attached to serine or threonine residues. O-GlcNAc is important for many cellular processes including nutrient sensing pathways, transcriptional regulation, and protein stability and turnover. Dysregulation of O-GlcNAc is further involved in diseases such as diabetes, neurodegeneration, and cancer. O-GlcNAcylation is highly dynamic and tightly regulated in response to a variety of environmental and physiological cues. In mammalian cells, the balance of O-GlcNAc is controlled by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). To understand how OGT dynamically regulates O-GlcNAc in cells, several techniques such as genetic manipulation and small molecule inhibition have been employed. However, prolonged OGT knockdown can severely affect normal cellular function, cell cycle, and survival, while cells respond to small molecule inhibition by rapid upregulation of OGT to compensate. To overcome these limitations, we undertook an emerging strategy, small molecule-mediated proteosomal degradation, for controlling protein levels <i>in cellulo</i>. Herein we synthesized and evaluated bifunctional molecules that can recruit an E3 ligase to OGT and efficiently degrade OGT in cells. The optimized bifunctional molecule was functionally evaluated for biological effects during T cell activation. We further used our Isotope Targeted Glycoproteomics (IsoTaG) platform in conjunction with OGT degradation to characterize the dynamics of O-GlcNAcome. OGT degradation via this new chemical tool opens new opportunities to study OGT function that can be widely applied to study many biological processes in which OGT plays a key role.<br/>

Development of an O-GlcNAc transferase (OGT) degrader for rapid control of OGT homeostasis

2019 Fall National Meeting

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