Research

The cycling of O-GlcNAc is tightly regulated by the coordinated actions of two enzymes encoded by distinct genes: O-GlcNAc transferase (OGT), which adds O-GlcNAc, and O-GlcNAcase (OGA), which removes it. While the abundance and glycosyltransferase activity of OGT and OGA are modulated through mRNA maturation and post-translational modifications (PTMs), substrate selection is primarily dictated by protein–protein interactions. Our research focuses on elucidating these regulatory mechanisms, particularly in models of oxidative stress and myocardial ischemia–reperfusion injury. To identify key substrates and regulators of OGT and OGA under basal conditions and in response to oxidative stress, we have employed both proximity ligation assays and native immunoprecipitation approaches coupled to mass spectrometry (Groves et al., J Biol Chem, 2017; Martinez et al., Mol Cell Proteomics, 2021). These studies revealed the OGT and OGA interactomes are remodeled during injury and that Fatty Acid Synthase functions as a protein inhibitor of OGA during injury. More recently, we demonstrated that cardioprotective O-GlcNAc signaling is enhanced in female murine hearts due to increased OGT activity, highlighting a sex-specific regulation of this pathway in cardiac physiology (Narayanan et al., J Biol Chem, 2023). Ongoing projects aim to dissect how glucose availability, cellular injury, and protein interactions influence OGT substrate selectivity and enzymatic activity across the heart, brain, and liver.