1. Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy.
- Author
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Lei Y, Liu Q, Chen B, Wu F, Li Y, Dong X, Ma N, Wu Z, Zhu Y, Wang L, Fu Y, Liu Y, Song Y, Du M, Zhang H, Zhu J, Lyons TJ, Wang T, Hu J, Xu H, Chen M, Yan H, and Wang X
- Subjects
- Animals, Humans, Mice, Phosphorylation, Endothelial Cells metabolism, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Male, Retina metabolism, Mice, Inbred C57BL, Acetylglucosamine metabolism, Transcriptional Coactivator with PDZ-Binding Motif Proteins metabolism, Glucose metabolism, Cell Cycle Proteins metabolism, Disease Models, Animal, Glycosylation, Diabetic Retinopathy metabolism, Signal Transduction, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases genetics, N-Acetylglucosaminyltransferases metabolism, N-Acetylglucosaminyltransferases genetics, Hippo Signaling Pathway, YAP-Signaling Proteins metabolism
- Abstract
Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target., (© 2024. The Author(s).)
- Published
- 2024
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