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

Yi Lei, Qiangyun Liu, Binggui Chen, Fangfang Wu, Yiming Li, Xue Dong, Nina Ma, Ziru Wu, Yanfang Zhu, Lu Wang, Yuxin Fu, Yuming Liu, Yinting Song, Mei Du, Heng Zhang, Jidong Zhu, Timothy J. Lyons, Ting Wang, Junhao Hu, Heping Xu, Mei Chen, Hua Yan () and Xiaohong Wang ()
Additional contact information
Yi Lei: Tianjin Medical University General Hospital
Qiangyun Liu: Tianjin Medical University General Hospital
Binggui Chen: Tianjin Medical University
Fangfang Wu: Tianjin Medical University
Yiming Li: Tianjin Medical University General Hospital
Xue Dong: Tianjin Medical University General Hospital
Nina Ma: Tianjin Medical University
Ziru Wu: Tianjin Medical University
Yanfang Zhu: Tianjin Medical University General Hospital
Lu Wang: Tianjin Medical University
Yuxin Fu: Tianjin Medical University
Yuming Liu: Tianjin Medical University General Hospital
Yinting Song: Tianjin Medical University General Hospital
Mei Du: Tianjin Medical University General Hospital
Heng Zhang: School of Basic Medical Sciences, Tianjin Medical University
Jidong Zhu: Tianjin Medical University
Timothy J. Lyons: Division of Endocrinology, Diabetes and Metabolic Diseases at the Medical University of South Carolina
Ting Wang: Tianjin Medical University
Junhao Hu: Chinese Academy of Sciences
Heping Xu: The Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast
Mei Chen: The Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast
Hua Yan: Tianjin Medical University General Hospital
Xiaohong Wang: Tianjin Medical University General Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53601-x

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