Journal Article

Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy

Hu, Junhao, Xu, Heping, Li, Yiming, Ma, Nina, Zhu, Jidong, Wang, Xiaohong, Wang, Ting, Wu, Ziru, Du, Mei, Chen, Mei, Wu, Fangfang, Dong, Xue, Yan, Hua, Liu, Qiangyun, Fu, Yuxin, Liu, Yuming, Song, Yinting, Chen, Binggui, Wang, Lu, Lyons, Timothy J., Lei, Yi, Zhu, Yanfang, Zhang, Heng

2024

Overview

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. Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy (DR). This study reveals that O -GlcNAcylation, a nutrient-sensitive protein modification, drives vascular dysfunction in DR by stabilizing Hippo signaling key components YAP/TAZ. Targeting O -GlcNAc-YAP/TAZ shows therapeutic potential for mitigating DR pathology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 14/19 / 38/39 / 45/15 / 631/443/1338/16 / 631/92/458 / 692/699/3161/3175 / 82/51 / 82/58 / Acetylglucosamine - metabolism / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Angiogenesis / Animal models / Animals / Cell culture / Cell Cycle Proteins - metabolism / Diabetes / Diabetes mellitus / Diabetic retinopathy / Diabetic Retinopathy - metabolism / Disease Models, Animal / Endothelial cells / Endothelial Cells - metabolism / Glucose / Glucose - metabolism / Glycosylation / Hippo Signaling Pathway / Homeostasis / Humanities and Social Sciences / Humans / Male / Metabolic disorders / Metabolic rate / Mice / Mice, Inbred C57BL / Molecular modelling / multidisciplinary / N-Acetylglucosaminyltransferases - genetics / N-Acetylglucosaminyltransferases - metabolism / Nutrients / O-GlcNAcylation / Pathogenesis / Phosphorylation / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Retina - metabolism / Retinopathy / Science / Science (multidisciplinary) / Signal Transduction / Stabilization / Therapeutic targets / Transcription activation / Transcriptional Coactivator with PDZ-Binding Motif Proteins - metabolism / YAP-Signaling Proteins - metabolism / Yes-associated protein