O-GlcNAc modification of GSDMD attenuates LPS-induced endothelial cells pyroptosis
© 2023. The Author(s)..
OBJECTIVE: Increased O-linked β-N-acetylglucosamine (O-GlcNAc) stimulation has been reported to protect against sepsis associated mortality and cardiovascular derangement. Previous studies, including our own research, have indicated that gasdermin-D(GSDMD)-mediated endothelial cells pyroptosis contributes to sepsis-associated endothelial injury. This study explored the functions and mechanisms of O-GlcNAc modification on lipopolysaccharide (LPS)-induced pyroptosis and its effects on the function of GSDMD.
METHODS: A LPS-induced septic mouse model administrated with O-GlcNAcase (OGA) inhibitor thiamet-G (TMG) was used to assess the effects of O-GlcNAcylation on sepsis-associated vascular dysfunction and pyroptosis. We conducted experiments on human umbilical vein endothelial cells (HUVECs) by challenging them with LPS and TMG to investigate the impact of O-GlcNAcylation on endothelial cell pyroptosis and implications of GSDMD. Additionally, we identified potential O-GlcNAcylation sites in GSDMD by utilizing four public O-GlcNAcylation site prediction database, and these sites were ultimately established through gene mutation.
RESULTS: Septic mice with increased O-GlcNAc stimulation exhibited reduced endothelial injury, GSDMD cleavage (a marker of pyroptosis). O-GlcNAc modification of GSDMD mitigates LPS-induced pyroptosis in endothelial cells by preventing its interaction with caspase-11 (a human homologous of caspases-4/5). We also identified GSDMD Serine 338 (S338) as a novel site of O-GlcNAc modification, leading to decreased association with caspases-4 in HEK293T cells.
CONCLUSIONS: Our findings identified a novel post-translational modification of GSDMD and elucidated the O-GlcNAcylation of GSDMD inhibits LPS-induced endothelial injury, suggesting that O-GlcNAc modification-based treatments could serve as potential interventions for sepsis-associated vascular endothelial injury.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
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| Enthalten in: |
Inflammation research : official journal of the European Histamine Research Society ... [et al. - 73(2024), 1 vom: 11. Jan., Seite 5-17 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yu, Fan [VerfasserIn] |
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| Links: |
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| Themen: |
Caspases |
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| Anmerkungen: |
Date Completed 15.01.2024 Date Revised 15.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00011-023-01812-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM36454208X |
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| 100 | 1 | |a Yu, Fan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a O-GlcNAc modification of GSDMD attenuates LPS-induced endothelial cells pyroptosis |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 15.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a OBJECTIVE: Increased O-linked β-N-acetylglucosamine (O-GlcNAc) stimulation has been reported to protect against sepsis associated mortality and cardiovascular derangement. Previous studies, including our own research, have indicated that gasdermin-D(GSDMD)-mediated endothelial cells pyroptosis contributes to sepsis-associated endothelial injury. This study explored the functions and mechanisms of O-GlcNAc modification on lipopolysaccharide (LPS)-induced pyroptosis and its effects on the function of GSDMD | ||
| 520 | |a METHODS: A LPS-induced septic mouse model administrated with O-GlcNAcase (OGA) inhibitor thiamet-G (TMG) was used to assess the effects of O-GlcNAcylation on sepsis-associated vascular dysfunction and pyroptosis. We conducted experiments on human umbilical vein endothelial cells (HUVECs) by challenging them with LPS and TMG to investigate the impact of O-GlcNAcylation on endothelial cell pyroptosis and implications of GSDMD. Additionally, we identified potential O-GlcNAcylation sites in GSDMD by utilizing four public O-GlcNAcylation site prediction database, and these sites were ultimately established through gene mutation | ||
| 520 | |a RESULTS: Septic mice with increased O-GlcNAc stimulation exhibited reduced endothelial injury, GSDMD cleavage (a marker of pyroptosis). O-GlcNAc modification of GSDMD mitigates LPS-induced pyroptosis in endothelial cells by preventing its interaction with caspase-11 (a human homologous of caspases-4/5). We also identified GSDMD Serine 338 (S338) as a novel site of O-GlcNAc modification, leading to decreased association with caspases-4 in HEK293T cells | ||
| 520 | |a CONCLUSIONS: Our findings identified a novel post-translational modification of GSDMD and elucidated the O-GlcNAcylation of GSDMD inhibits LPS-induced endothelial injury, suggesting that O-GlcNAc modification-based treatments could serve as potential interventions for sepsis-associated vascular endothelial injury | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Endothelial | |
| 650 | 4 | |a GSDMD | |
| 650 | 4 | |a O-GlcNAc | |
| 650 | 4 | |a Pyroptosis | |
| 650 | 4 | |a Sepsis | |
| 650 | 7 | |a Caspases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Gasdermins |2 NLM | |
| 650 | 7 | |a GSDMD protein, human |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Phosphate-Binding Proteins |2 NLM | |
| 650 | 7 | |a Gsdmd protein, mouse |2 NLM | |
| 700 | 1 | |a Zhang, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Leng, Yiping |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Alex F |e verfasserin |4 aut | |
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