O-GlcNAcylation of intracellular proteins takes place via a single transfer of GlcNAc to the hydroxyl group of serine or threonine residues.O-GlcNAcylation modulates the extrinsic apoptotic ...pathway.To facilitate colonization of pathogens in host cells, bacterial effector proteins suppress death receptor (DR) signaling.Sustained increases in O-GlcNAcylation contribute to tumor development.
The importance of post-translational modifications (PTMs), particularly O-GlcNAcylation, of cytoplasmic proteins in apoptosis has been neglected for quite a while. Modification of cytoplasmic proteins by a single N-acetylglucosamine sugar is a dynamic and reversible PTM exhibiting properties more like phosphorylation than classical O- and N-linked glycosylation. Due to the sparse information existing, we have only limited understanding of how GlcNAcylation affects cell death. Deciphering the role of GlcNAcylation in cell fate may provide further understanding of cell fate decisions. This review focus on the modulation of extrinsic apoptotic pathway via GlcNAcylation carried out by O-GlcNAc transferase (OGT) or by other bacterial effector proteins.
The importance of post-translational modifications (PTMs), particularly O-GlcNAcylation, of cytoplasmic proteins in apoptosis has been neglected for quite a while. Modification of cytoplasmic proteins by a single N-acetylglucosamine sugar is a dynamic and reversible PTM exhibiting properties more like phosphorylation than classical O- and N-linked glycosylation. Due to the sparse information existing, we have only limited understanding of how GlcNAcylation affects cell death. Deciphering the role of GlcNAcylation in cell fate may provide further understanding of cell fate decisions. This review focus on the modulation of extrinsic apoptotic pathway via GlcNAcylation carried out by O-GlcNAc transferase (OGT) or by other bacterial effector proteins.
O-GlcNAcylation is an essential protein glycosylation governed by two O-GlcNAc cycling enzymes: O-GlcNAc transferase (OGT) installs a single sugar moiety N-acetylglucosamine (GlcNAc) on protein ...serine and threonine residues, and O-GlcNAcase (OGA) removes them. Aberrant O-GlcNAcylation has been implicated in various diseases. However, the large repertoire of more than 1000 O-GlcNAcylated proteins and the elusive mechanisms of OGT/OGA in substrate recognition present significant challenges in targeting the dysregulated O-GlcNAcylation for therapeutic development. Recently, emerging evidence suggested that the non-catalytic domains play critical roles in regulating the functional specificity of OGT/OGA via modulating their protein interactions and substrate recognition. Here, we discuss recent studies on the structures, mechanisms, and related tools of the OGT/OGA non-catalytic domains, highlighting new opportunities for function-specific control.
The dynamic post‐translational modification of serine or threonine residues by O‐linked N‐acetyl‐beta‐D‐glucosamine (O‐GlcNAc) contributes to diverse cellular processes including epigenetic ...modifications, transcription, metabolism, and cell signaling that play significant roles in development and normal physiology. O‐GlcNAcylation is catalyzed by O‐GlcNAc transferase and the modification is removed by O‐GlcNAcase (OGA). These genes are highly regulated at multiple levels, but little is known about their regulation by microRNAs (miRs). miRs are small non‐coding RNAs that fine‐tune protein expression through binding to messenger RNA (mRNA). In this work, we built a comprehensive dataset of OGT and OGA regulation via both their 3’UTR and 5’UTRs. Downregulation was almost exclusively mediated through binding to the 3’UTR. We observed independent regulation of OGT and OGA by the majority of regulatory miRs, which did not overlap. However, we did see significant co‐regulation of OGT and OGA by a subset of miRs. This is in keeping with the known transcriptional regulation of these genes.
In summary, this work provides a better understanding of OGT and OGA regulation through miRNA binding via both the 3’UTR and 5’UTR regions.
The neurofibrillary tangles (NFTs) formed from hyperphosphorylation of tau protein are closely associated with Alzheimer's disease (AD). O-GlcNAcylation of tau can negatively regulate ...hyperphosphorylation and the O-GlcNAcase (OGA) catalyzes the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from tau protein. Therefore, preventing tau hyperphosphorylation by increasing the levels of tau O-GlcNAcylation via OGA inhibitors could be a promising approach. Based on Thiamet-G, a potent OGA inhibitor, and its binding mode to OGA, a novel OGA inhibitor scaffold bearing three parts was designed and hit compound 7j was successfully identified via extensive exploring. Further chemical optimization and diversification of the 7j structure resulted in compound 39 which possesses excellent OGA inhibition, no cytotoxicity, and has good pharmacokinetic properties. In acute AD model mice, 39 was more effective than Thiamet-G in inhibiting OGA activity attributable to its better blood-brain barrier permeability. In addition, 39 restored the cognitive function in mice and reduced amyloid-β (Aβ) concentrations to a greater extent than Thiamet-G. Molecular docking studies demonstrated that 39 was well associated with OGA through H-bonds and hydrophobic interaction. Together, these findings suggest that 39 was promising as a potent OGA inhibitor in the treatment of AD.
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•Non-sugar OGA inhibitors were designed and synthesized based on Thimet-G.•Most synthetic compounds showed good OGA inhibitory activity and selectivity.•Selected compounds possessed excellent blood-brain barrier (BBB) permeability.•39 with an IC50 value of 40 nM displayed suitable PK properties, inhibited OGA activity, restored cognitive function in mice.
Modification of nucleocytoplasmic proteins with O-GlcNAc regulates a wide variety of cellular processes and has been linked to human diseases. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase ...(OGA) add and remove O-GlcNAc, but the mechanisms regulating their expression remain unclear. Here, we demonstrate that retention of the fourth intron of OGT is regulated in response to O-GlcNAc levels. We further define a conserved intronic splicing silencer (ISS) that is necessary for OGT intron retention. Deletion of the ISS in colon cancer cells leads to increases in OGT, but O-GlcNAc homeostasis is maintained by concomitant increases in OGA protein. However, the ISS-deleted cells are hypersensitive to OGA inhibition in culture and in soft agar. Moreover, growth of xenograft tumors from ISS-deleted cells is compromised in mice treated with an OGA inhibitor. Thus, ISS-mediated regulation of OGT intron retention is a key component in OGT expression and maintaining O-GlcNAc homeostasis.
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•O-GlcNAc transferase (OGT) expression is regulated by intron retention•OGT intron retention dynamically responds to O-GlcNAc levels•A conserved intronic splicing silencer (ISS) regulates OGT expression•The OGT-ISS is necessary for maintaining O-GlcNAc homeostasis
O-GlcNAc transferase (OGT) modifies cellular proteins, but the mechanisms that regulate OGT expression remain unclear. Park et al. show intron retention of the OGT transcript is responsive to cellular O-GlcNAc levels. They further define an intronic splicing silencer that is necessary to maintain O-GlcNAc homeostasis in cells and tumors.
O-GlcNAcylation is a post-translational modification of proteins that involves the addition of O-GlcNAc to serine or threonine residues of nuclear or cytoplasmic proteins, catalyzed by O-GlcNAc ...transferase (OGT). This modification is highly dynamic and can be reversed by O-GlcNAcase (OGA). O-GlcNAcylation is widespread in the immune system, which engages in multiple physiologic and pathophysiologic processes. There is substantial evidence indicating that both the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation are critically involved in regulating immune cell function. However, the precise role of O-GlcNAcylation in the immune system needs to be adequately elucidated. This review offers a thorough synopsis of the present research on protein O-GlcNAcylation, accentuating the molecular mechanisms that control immune cells’ growth, maturation, and performance
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this PTM.
Thousands of nuclear and cytosolic proteins are modified with a single β-N-acetylglucosamine on serine and threonine residues in mammals, a modification termed O-GlcNAc. This modification is ...essential for normal development and plays important roles in virtually all intracellular processes. Additionally, O-GlcNAc is involved in many disease states, including cancer, diabetes, and X-linked intellectual disability. Given the myriad of functions of the O-GlcNAc modification, it is therefore somewhat surprising that O-GlcNAc cycling is mediated by only two enzymes: the O-GlcNAc transferase (OGT), which adds O-GlcNAc, and the O-GlcNAcase (OGA), which removes it. A significant outstanding question in the O-GlcNAc field is how do only two enzymes mediate such an abundant and dynamic modification. In this review, we explore the current understanding of mechanisms for substrate selection for the O-GlcNAc cycling enzymes. These mechanisms include direct substrate interaction with specific domains of OGT or OGA, selection of interactors via partner proteins, posttranslational modification of OGT or OGA, nutrient sensing, and localization alteration. Altogether, current research paints a picture of an exquisitely regulated and complex system by which OGT and OGA select substrates. We also make recommendations for future work, toward the goal of identifying interaction mechanisms for specific substrates that may be able to be exploited for various research and medical treatment goals.
Understanding the regulation of human embryonic stem cells (hESCs) pluripotency is critical to advance the field of developmental biology and regenerative medicine. Despite the recent progress, ...molecular events regulating hESC pluripotency, especially the transition between naive and primed states, still remain unclear. Here we show that naive hESCs display lower levels of O-linked N-acetylglucosamine (O-GlcNAcylation) than primed hESCs. O-GlcNAcase (OGA), the key enzyme catalyzing the removal of O-GlcNAc from proteins, is highly expressed in naive hESCs and is important for naive pluripotency. Depletion of OGA accelerates naive-to-primed pluripotency transition. OGA is transcriptionally regulated by EP300 and acts as a transcription regulator of genes important for maintaining naive pluripotency. Moreover, we profile protein O-GlcNAcylation of the two pluripotency states by quantitative proteomics. Together, this study identifies OGA as an important factor of naive pluripotency in hESCs and suggests that O-GlcNAcylation has a broad effect on hESCs homeostasis.
•OGA is highly expressed in naive hESCs and is important for naive pluripotency•Depletion of OGA accelerates naive-to-primed transition•OGA is transcriptionally regulated by EP300 in naive hESCs•OGA acts as a transcription regulator of genes important for naive pluripotency
Liu et al. showed that O-GlcNAcase (OGA) is highly expressed in naive hESCs and is important for naive pluripotency. Depleting OGA accelerates naive-to-primed transition. OGA acts as a transcription regulator of genes important for maintaining naive pluripotency. Together, this study identifies OGA as an important factor of naive pluripotency in hESCs and suggests that O-GlcNAcylation has a broad effect on hESCs homeostasis.
O-linked β-D-N-acetylglucosamine (O-GlcNAc), as a posttranslational modification (PTM), is a reversible reaction that attaches β-N-GlcNAc to Ser/Thr residues on specific proteins by O-GlcNAc ...transferase (OGT). O-GlcNAcase (OGA) removes the O-GlcNAc from O-GlcNAcylated proteins. O-GlcNAcylation regulates numerous cellular processes, including signal transduction, the cell cycle, metabolism, and energy homeostasis. Dysregulation of O-GlcNAcylation contributes to the development of various diseases, including cancers. Accumulating evidence has revealed that higher expression levels of OGT and hyper-O-GlcNAcylation are detected in many cancer types and governs glucose metabolism, proliferation, metastasis, invasion, angiogenesis, migration and drug resistance. In this review, we describe the biological functions and molecular mechanisms of OGT- or O-GlcNAcylation-mediated tumorigenesis. Moreover, we discuss the potential role of O-GlcNAcylation in tumor immunotherapy. Furthermore, we highlight that compounds can target O-GlcNAcylation by regulating OGT to suppress oncogenesis. Taken together, targeting protein O-GlcNAcylation might be a promising strategy for the treatment of human malignancies.
•Dysregulation of O-GlcNAcylation participates into the tumorigenesis and progression.•O-GlcNAcylation plays a pivotal role in tumor immunotherapy.•Compounds target O-GlcNAcylation by regulating OGT to suppress oncogenesis.•Targeting protein O-GlcNAcylation might be a promising strategy for cancer treatment.
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