July
25,
2024
Ao Wang, Pharmaceutical Sciences graduate student (Jiang Lab), will be defending her PhD research thesis:
O-Linked β-N-acetylglucosamine (O-GlcNAcylation) is a dynamic post-translational modification that regulates numerous proteins critical for cellular functions. O-GlcNAcase (OGA), the sole enzyme responsible for removing O-GlcNAc modifications, regulates over thousands of protein substrates in cells without a consensus motif for substrate recognition. OGA undergoes cleavage by caspase-3 during apoptosis, leaving two fragments at D413 residue. Remarkably, OGA can be also O-GlcNAcylated at S405 residue in close proximity to this cleavage site. In this defense, we demonstrated that cleaved OGA exhibits a distinct substrate preference in vitro though the cleaved fragments remain associated and catalytically active towards 4MU-GlcNAc. Besides, O-GlcNAcylation of OGA at S405 impedes its cleavage by caspase-3, which can inhibit the cell death in apoptosis by modulating the activities of caspases involved in both extrinsic and intrinsic apoptosis pathways. Our research reveals a novel regulatory mechanism whereby O-GlcNAcylation safeguards OGA from caspase-3 cleavage, intricately tuning apoptosis dynamics. Furthermore, OGA has a broad impact in many diseases including cancer. However, its role in cell malignancy remains largely unknown. Herein, we identified a cancer-derived point mutation at OGA stalk domain dysregulated the protein-protein interaction and substrate deglycosylation of a specific set of protein substrates. Interestingly, we found that the cancer-derived OGA mutant aberrantly deglycosylated PDZ and LIM domain protein 7 (PDLIM7) leading to the downregulated cancer suppressor p53 and further promoted cancer cell malignancy. Moreover, deglycosylated PDLIM7 significantly enhanced the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. Taken together, these findings provide new insights into the regulation and impact of O-GlcNAcylation, broadening the comprehension of its role in cellular function and disease progression/p>
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