Spatial and temporal proteomics reveals the distinct distributions and dynamics of O-GlcNAcylated proteins

Xu, Senhan; Tong, Ming Him; Suttapitugsakul, Suttipong; Wu, Ronghu

doi:10.1016/j.celrep.2022.110946

Cited by 18 publications

(20 citation statements)

References 101 publications

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“…Mutations of related binding residues on the glycopeptide or OGA cleft surface impaired their interaction, suggesting that OGA is capable of recognizing specific features of glycosylated substrates beyond the O-GlcNAc moiety. This hypothesis is in line with the quantitative proteomic analysis, which detected a broad range of O-GlcNAc half-lives on different protein substrates as responding to OGA activity in human leukemia Jurkat cells [ 76 ]. Taken together, these structural and proteomic results support that protein interactions with the OGA substrate-binding cleft do exist and can contribute to OGA substrate binding and discrimination.…”

Section: Structural Insights Of O-glcnac Cycling Enzymes As Potential...supporting

confidence: 66%

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

Xie

Jiang

2022

Cancers

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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.

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Section: Structural Insights Of O-glcnac Cycling Enzymes As Potential...supporting

confidence: 66%

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

Xie

Jiang

2022

Cancers

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“…The O -GlcNAc modification is responsive to environmental changes , and also possesses distinct compartment-specific dynamics in the cell. , Correspondingly, OGA is a nucleocytoplasmic enzyme, whereas the long-spliced OGT primarily localizes in the nucleus . We therefore sought to extend the 4-HT-triggered OGA–intein activation strategy for controllable spatial deglycosylation.…”

Section: Resultsmentioning

confidence: 99%

“…The O -GlcNAc modification is orchestrated by a single pair of enzymes, O -GlcNAc transferase (OGT) for installation and O -GlcNAcase (OGA) for removal. These enzymes dynamically regulate O -GlcNAc and hence many fundamental cellular processes in a spatiotemporal manner, which respond to fluctuating nutrient levels, stresses, and signaling stimuli. , Maintenance of O -GlcNAc homeostasis is crucial for regular cellular activities, which is achieved through multiple mechanisms, including translational , and transcriptional regulation. , Not surprisingly, abnormal O -GlcNAcylation is implicated in many diseases. − For example, many of these O -GlcNAcylated proteins are known to be associated with oncogenesis . A persistent hyper- O -GlcNAcylation state is commonly observed in various cancers, such as breast, prostate, and lung, implying a potential role in tumor progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…These enzymes dynamically regulate O-GlcNAc and hence many fundamental cellular processes in a spatiotemporal manner, which respond to fluctuating nutrient levels, stresses, and signaling stimuli. 1,2 Maintenance of O-GlcNAc homeostasis is crucial for regular cellular activities, which is achieved through multiple mechanisms, including translational 3,4 and transcriptional regulation. 5,6 Not surprisingly, abnormal O-GlcNAcylation is implicated in many diseases.…”

Section: ■ Introductionmentioning

confidence: 99%

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Small Molecule-Activated O-GlcNAcase for Spatiotemporal Removal of O-GlcNAc in Live Cells

Yang

et al. 2023

ACS Chem. Biol.

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The nutrient sensor O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification found on thousands of nucleocytoplasmic proteins. O-GlcNAc levels in cells dynamically respond to environmental cues in a temporal and spatial manner, leading to altered signal transduction and functional effects. The spatiotemporal regulation of O-GlcNAc levels would accelerate functional interrogation of O-GlcNAc and manipulation of cell behaviors for desired outcomes. Here, we report a strategy for spatiotemporal reduction of O-GlcNAc in live cells by designing an O-GlcNAcase (OGA) fused to an intein triggered by 4-hydroxytamoxifen (4-HT). After rational protein engineering and optimization, we identified an OGA–intein variant whose deglycosidase activity can be triggered in the desired subcellular compartments by 4-HT in a time- and dose-dependent manner. Finally, we demonstrated that 4-HT activation of the OGA–intein fusion can likewise potentiate inhibitory effects in breast cancer cells by virtue of the reduction of O-GlcNAc. The spatiotemporal control of O-GlcNAc through the chemically activatable OGA–intein fusion will facilitate the manipulation and functional understanding of O-GlcNAc in live cells.

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“…O -GlcNAcylation exists in almost all living organisms, and it is distributed in almost all human tissues, even in saliva and urine [ 18 ]. O -GlcNAcylation occurs in almost all cellular compartments, and its first discovery in 1984 overturned the conventional knowledge that glycosylation occurs only in the endoplasmic reticulum and Golgi apparatus [ 19 ]. It also shows that almost all functions of proteins in regulating various cellular processes are covered.…”

Section: Introductionmentioning

confidence: 99%

Protein O-GlcNAcylation in Metabolic Modulation of Skeletal Muscle: A Bright but Long Way to Go

Liu

2022

Metabolites

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O-GlcNAcylation is an atypical, dynamic and reversible O-glycosylation that is critical and abundant in metazoan. O-GlcNAcylation coordinates and receives various signaling inputs such as nutrients and stresses, thus spatiotemporally regulating the activity, stability, localization and interaction of target proteins to participate in cellular physiological functions. Our review discusses in depth the involvement of O-GlcNAcylation in the precise regulation of skeletal muscle metabolism, such as glucose homeostasis, insulin sensitivity, tricarboxylic acid cycle and mitochondrial biogenesis. The complex interaction and precise modulation of O-GlcNAcylation in these nutritional pathways of skeletal muscle also provide emerging mechanical information on how nutrients affect health, exercise and disease. Meanwhile, we explored the potential role of O-GlcNAcylation in skeletal muscle pathology and focused on its benefits in maintaining proteostasis under atrophy. In general, these understandings of O-GlcNAcylation are conducive to providing new insights into skeletal muscle (patho) physiology.

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Spatial and temporal proteomics reveals the distinct distributions and dynamics of O-GlcNAcylated proteins

Cited by 18 publications

References 101 publications

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

Small Molecule-Activated O-GlcNAcase for Spatiotemporal Removal of O-GlcNAc in Live Cells

Protein O-GlcNAcylation in Metabolic Modulation of Skeletal Muscle: A Bright but Long Way to Go

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