O-GlcNAc transferase is a unique and fundamentally important glycosyltransferase found in all multicellular organisms. Whereas other glycosyltransferases act in the ER/Golgi compartments to assemble cell surface glycoproteins and proteoglycans, OGT glycosylates serines and threonines of nuclear and cytoplasmic proteins. These O-GlcNAc modifications are removed by a glycosidase called OGA, and it has been observed that protein O-GlcNAc levels change in response to stress, nutrient conditions and other inputs. Based on these and other observations, OGT is proposed to play a crucial role in cell signaling. Signaling changes often occur on very short timescales and so studying them requires methods to acutely perturb protein activity. Inhibitors are a standard way to perturb activity, but the development of cell permeable and specific glycosyltransferase inhibitors has been a major challenge in the carbohydrate field. Here we will describe our discovery of cell permeable OGT inhibitors that bind with low nanomolar Kds. These inhibitors are not based on substrates and what we have learned about how they bind may inform development of inhibitors for other glycosyltransferases. We will then describe how we have used these inhibitors along with OGA inhibitors to uncover an unexpected role for O-GlcNAc in global regulation of detained intron splicing. We conclude that O-GlcNAc signaling acts, in part, to control mRNA abundance through post-transcriptional mechanisms.

Small-molecule inhibitors reveal that O-GlcNAc signaling globally regulates mRNA splicing

2019 Fall National Meeting

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