The dynamic O-GlcNAc modification of intracellular proteins is an important nutrient sensor for integrating metabolic signals into vast networks of highly coordinated cellular activities. Dysregulation of the sole enzymes responsible for O-GlcNAc cycling, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), and the associated cellular O-GlcNAc profile is a common feature across nearly every cancer type. Many studies have investigated the effects of aberrant OGT/OGA expression on global O-GlcNAcylation activity in cancer cells. However, recent studies have begun to elucidate the roles of protein–protein interactions (PPIs), potentially through regions outside of the immediate catalytic site of OGT/OGA, that regulate greater protein networks to facilitate substrate-specific modification, protein translocalization, and the assembly of larger biomolecular complexes. Perturbation of OGT/OGA PPI networks makes profound changes in the cell and may directly contribute to cancer malignancies. Herein, we highlight recent studies on the structural features of OGT and OGA, as well as the emerging roles and molecular mechanisms of their aberrant PPIs in rewiring cancer networks. By integrating complementary approaches, the research in this area will aid in the identification of key protein contacts and functional modules derived from OGT/OGA that drive oncogenesis and will illuminate new directions for anti-cancer drug development.
The modification of intracellular proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) moieties is a highly dynamic process that spatiotemporally regulates nearly every important cellular program. Despite its significance, little is known about the substrate recognition and regulation modes of O-GlcNAc transferase (OGT), the primary enzyme responsible for O-GlcNAc addition. In this study, we have identified the intervening domain (Int-D), a poorly understood protein fold found only in metazoan OGTs, as a specific regulator of OGT protein-protein interactions and substrate modification. Utilizing an innovative proteomic peptide phage display (ProP-PD) coupled with structural, biochemical, and cellular characterizations, we discovered a novel peptide motif, employed by the Int-D to facilitate specific O-GlcNAcylation. We further show that disruption of Int-D binding dysregulates important cellular programs including nutrient stress response and glucose metabolism. These findings illustrate a novel mode of OGT substrate recognition and offer the first insights into the biological roles of this unique domain.
O-GlcNAcase (OGA) is the sole enzyme that hydrolyzes O-GlcNAcylation from thousands of proteins and is dysregulated in many diseases including cancer. However, the substrate recognition and pathogenic mechanisms of OGA remain largely unknown. Here we report the first discovery of a cancer-derived point mutation on the OGA’s non-catalytic stalk domain that aberrantly regulated a small set of OGA-protein interactions and O-GlcNAc hydrolysis in critical cellular processes. We uncovered a novel cancer-promoting mechanism in which the OGA mutant preferentially hydrolyzed the O-GlcNAcylation from modified PDLIM7 and promoted cell malignancy by down-regulating p53 tumor suppressor in different types of cells through transcription inhibition and MDM2-mediated ubiquitination. Our study revealed the OGA deglycosylated PDLIM7 as a novel regulator of p53-MDM2 pathway, offered the first set of direct evidence on OGA substrate recognition beyond its catalytic site, and illuminated new directions to interrogate OGA’s precise role without perturbing global O-GlcNAc homeostasis for biomedical applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.