Protein O-GlcNAcylation: emerging mechanisms and functions

Yang, Xiaoyong; Qian, Kevin

doi:10.1038/nrm.2017.22

Cited by 857 publications

(925 citation statements)

References 165 publications

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“…This inability to activate O‐GlcNAcylation after CA/CPR may have a major impact on outcome, as is suggested in current literature. O‐GlcNAcylation regulates the function of many proteins, and protects cells in a variety of stress environments 35. In the heart, activation of O‐GlcNAcylation protects against the calcium paradox and ischemic damage, and also blocks ischemic stress–induced mitochondrial calcium overload and loss of membrane potential 36.…”

Section: Discussionmentioning

confidence: 99%

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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BackgroundThe mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after CA.Methods and ResultsYoung (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation (CPR). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA/CPR‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After CA/CPR, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after CA/CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after CA improved outcome.ConclusionsResults suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA/CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after CA/CPR may represent a promising therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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“…HBP has been considered as a minor glucose metabolism pathway, since only 2–5% of the glucose that enters cells is directed to this pathway, eventually leading to the generation of its end product uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) (Hardiville and Hart, 2014). O -GlcNAc transferase (OGT) mediates the transfer of UDP-GlcNAc to serine or threonine residue of target proteins, known as protein O -GlcNAcylation (Levine and Walker, 2016; Yang and Qian, 2017). Previous studies have discovered essential roles of HBP and protein O- GlcNAcylation in many fundamental biological activities (Bond and Hanover, 2013; Hart et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

Attri

et al. 2018

Cell Host & Microbe

120

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SUMMARY Increased glucose metabolism in immune cells not only serves as a hallmark feature of acute inflammation, but also profoundly affects disease outcome following bacterial infection and tissue damage. However, the role of individual glucose metabolic pathways during viral infection remains largely unknown. Here we demonstrate an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in promoting antiviral innate immunity. Challenge of macrophages with vesicular stomatitis viruses (VSV) enhances HBP activity and downstream protein O-GlcNAcylation. Human and murine cells deficient of O-GlcNAc transferase, a key enzyme for protein O-GlcNAcylation, show defective antiviral immune responses upon VSV challenge. Mechanistically, OGT-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 (S366) is required for K63-linked ubiquitination of MAVS and subsequent downstream RLR-antiviral signaling activation. Thus, our study identifies a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates MAVS function and highlights the importance of glucose metabolism on antiviral innate immunity.

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“…This modification is a reversible process regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) for addition and removal of GlcNAc residue from target proteins [12]. This modification is a reversible process regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) for addition and removal of GlcNAc residue from target proteins [12].…”

Section: Introductionmentioning

confidence: 99%

New evidence of connections between increased O-GlcNAcylation and inflammasome in the oral mucosa of patients with oral lichen planus

Thi

Phoomak

Champattanachai

et al. 2018

Clinical and Experimental Immunology

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Oral lichen planus (OLP) is considered a chronic inflammatory immune-mediated disease of the oral mucosa. Immunopathogenesis of OLP is thought to be associated with cell-mediated immune dysregulation. O-GlcNAcylation is a form of reversible glycosylation. It has been demonstrated that O-GlcNAcylation promoted nuclear factor kappa B (NF-κB) signalling. Activation of NF-кB can induce expression of nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is a large intracellular multi-protein complex involving an immune response. Dysregulated expression of the NLRP3 inflammasome was reported to be associated with autoinflammatory diseases. No integrative studies between O-GlcNAcylation and NLRP3 inflammasome in OLP patients have been reported. The present study aimed to determine the immunohistochemical expression of O-GlcNAcylation, NF-κB signalling molecules and NLRP3 inflammasome in oral mucosae of OLP patients. Oral tissue samples were collected from 30 OLP patients and 30 healthy individuals. Immunohistochemical staining and analyses of immunostaining scores were performed to evaluate expression of O-GlcNAcylation, NF-κB signalling molecules and NLRP3 inflammasome. According to observations in this study, significantly higher levels of O-GlcNAcylation, NF-κB signalling molecules and NLRP3 inflammasome were demonstrated in OLP patients compared with control subjects (P < 0·001). Positive correlations among O-GlcNAcylation, NF-κB signalling molecules and NLRP3 inflammasome were also observed in OLP samples (P < 0·01). In conclusion, the present study provides supportive evidence that increased O-GlcNAcylation is associated with increased expression of NLRP3 inflammasome via the NF-κB signalling pathway. These findings provide a new perspective on immunopathogenesis of OLP in relation to autoinflammation.

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Protein O-GlcNAcylation: emerging mechanisms and functions

Cited by 857 publications

References 165 publications

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

New evidence of connections between increased O-GlcNAcylation and inflammasome in the oral mucosa of patients with oral lichen planus

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