{"title":"O-GlcNAc transferase mediates O-GlcNAcylation of NLRP3 regulates pyroptosis in spinal cord injury","authors":"Zhichao Zeng, Xuqiang Liao, Xinjian Zhao","doi":"10.1016/j.brainresbull.2025.111233","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Spinal cord injury (SCI) represents a severe disorder of the nervous system, imposing significant physical, psychological, and socioeconomic burdens on affected individuals and society.</div></div><div><h3>Objective</h3><div>We investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAcylation) in regulating pyroptosis related proteins at the posttranslational level.</div></div><div><h3>Materials and methods</h3><div>PC12 cells were stimulated with lipopolysaccharide (LPS). The O-GlcNAcylation pathway was modified by manipulating the expression of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Pro-inflammatory cytokine levels and cell pyroptosis were assessed. Co-immunoprecipitation (Co-IP) assays were employed to investigate the interaction between NLRP3 and OGT. For <em>in vivo</em> studies, an established SCI rat model was utilized. Levels of pro-inflammatory factors, NLRP3 inflammasome components, and proteins associated with pyroptosis were measured.</div></div><div><h3>Results</h3><div>Both O-GlcNAc levels and OGT expression were significantly elevated in the SCI model cells. Inhibition of OGT led to a marked reduction in the levels of pro-inflammatory cytokines and a suppression of pyroptosis. Furthermore, inhibition of OGT resulted in downregulation of NLRP3 and its O-GlcNAcylation, while overexpression of OGT produced the opposite effect. We verified the endogenous and exogenous interactions between NLRP3 and OGT. Importantly, knockout of OGT mitigated the progression of SCI in an animal model, suggesting a protective role of OGT inhibition in SCI.</div></div><div><h3>Discussion and conclusion</h3><div>This study preliminarily proved that the mechanism of OGT mediated O-GlcNAcylation of NLRP3 participates in the action of pyroptosis in SCI. Targeting OGT and NLRP3 may be novel therapy method in SCI.</div></div>","PeriodicalId":9302,"journal":{"name":"Brain Research Bulletin","volume":"222 ","pages":"Article 111233"},"PeriodicalIF":3.7000,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Research Bulletin","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0361923025000450","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Spinal cord injury (SCI) represents a severe disorder of the nervous system, imposing significant physical, psychological, and socioeconomic burdens on affected individuals and society.
Objective
We investigated the implication of O-linked β-N-acetylglucosamine (O-GlcNAcylation) in regulating pyroptosis related proteins at the posttranslational level.
Materials and methods
PC12 cells were stimulated with lipopolysaccharide (LPS). The O-GlcNAcylation pathway was modified by manipulating the expression of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Pro-inflammatory cytokine levels and cell pyroptosis were assessed. Co-immunoprecipitation (Co-IP) assays were employed to investigate the interaction between NLRP3 and OGT. For in vivo studies, an established SCI rat model was utilized. Levels of pro-inflammatory factors, NLRP3 inflammasome components, and proteins associated with pyroptosis were measured.
Results
Both O-GlcNAc levels and OGT expression were significantly elevated in the SCI model cells. Inhibition of OGT led to a marked reduction in the levels of pro-inflammatory cytokines and a suppression of pyroptosis. Furthermore, inhibition of OGT resulted in downregulation of NLRP3 and its O-GlcNAcylation, while overexpression of OGT produced the opposite effect. We verified the endogenous and exogenous interactions between NLRP3 and OGT. Importantly, knockout of OGT mitigated the progression of SCI in an animal model, suggesting a protective role of OGT inhibition in SCI.
Discussion and conclusion
This study preliminarily proved that the mechanism of OGT mediated O-GlcNAcylation of NLRP3 participates in the action of pyroptosis in SCI. Targeting OGT and NLRP3 may be novel therapy method in SCI.
期刊介绍：
The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.
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