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

Diabetic Retinopathy / metabolism Animals Humans Signal Transduction Protein Serine-Threonine Kinases / metabolism N-Acetylglucosaminyltransferases / metabolism Mice Hippo Signaling Pathway Phosphorylation YAP-Signaling Proteins / metabolism Endothelial Cells / metabolism Adaptor Proteins, Signal Transducing / metabolism 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

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
29 Oct 2024
Historique:
received: 10 08 2023
accepted: 17 10 2024
medline: 30 10 2024
pubmed: 30 10 2024
entrez: 30 10 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-53601-x PMID: 39472558
pubmed: 39472558
doi: 10.1038/s41467-024-53601-x
pii: 10.1038/s41467-024-53601-x
doi:

Substances chimiques

Protein Serine-Threonine Kinases EC 2.7.11.1
N-Acetylglucosaminyltransferases EC 2.4.1.-
O-GlcNAc transferase EC 2.4.1.-
YAP-Signaling Proteins 0
Adaptor Proteins, Signal Transducing 0
Acetylglucosamine V956696549
Transcriptional Coactivator with PDZ-Binding Motif Proteins 0
Glucose IY9XDZ35W2
Cell Cycle Proteins 0
YAP1 protein, human 0
Wwtr1 protein, mouse 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

9334

Subventions

Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82122018
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 32171101
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 8230041151
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82020108007
Organisme : Natural Science Foundation of Tianjin City (Natural Science Foundation of Tianjin)
ID : 23JCJQJC00050

Informations de copyright

© 2024. The Author(s).

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Auteurs

Yi Lei (Y)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.
Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
ORCID: 0000-0001-9596-3472

Qiangyun Liu (Q)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.

Binggui Chen (B)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Fangfang Wu (F)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Yiming Li (Y)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.

Xue Dong (X)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.
Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Nina Ma (N)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Ziru Wu (Z)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
ORCID: 0009-0005-5091-6089

Yanfang Zhu (Y)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.

Lu Wang (L)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Yuxin Fu (Y)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Yuming Liu (Y)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.
ORCID: 0009-0001-3392-1362

Yinting Song (Y)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.

Mei Du (M)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.
Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Heng Zhang (H)

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
ORCID: 0000-0003-1112-7149

Jidong Zhu (J)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Timothy J Lyons (TJ)

Division of Endocrinology, Diabetes and Metabolic Diseases at the Medical University of South Carolina, Charleston, SC, USA.
ORCID: 0000-0003-2106-1622

Ting Wang (T)

Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
ORCID: 0000-0003-2257-0699

Junhao Hu (J)

Laboratory of Vascular Biology and Organ Homeostasis, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
ORCID: 0000-0003-0699-1119

Heping Xu (H)

The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
ORCID: 0000-0003-4000-931X

Mei Chen (M)

The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.

Hua Yan (H)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China. zyyyanhua@tmu.edu.cn.
School of Medicine, Nankai University, Tianjin, China. zyyyanhua@tmu.edu.cn.
ORCID: 0000-0002-7651-840X

Xiaohong Wang (X)

Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China. xiaohongwang@tmu.edu.cn.
Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. xiaohongwang@tmu.edu.cn.
ORCID: 0000-0001-8628-243X

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Classifications MeSH

questionsmedicales.fr › Maladies endocriniennes › Diabète › Complications du diabète › Angiopathies diabétiques › Rétinopathie diabétique › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Eucaryotes › Animaux › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Glycosyltransferase › N-acetylhexosaminyltransferase › N-acetylglucosaminyltransferase › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Hippo › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Métabolisme › Phosphorylation › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Organes des sens › Oeil › Rétine › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Glucides › Osamines › Hexosamine › Glucosamine › Acétyl-glucosamine › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Transcriptional coactivator with PDZ-binding motif proteins › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Glucides › Sucres › Oses › Hexose › Glucose › Protein O-GlcNAcylation coupled to Hippo...
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questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Protein O-GlcNAcylation coupled to Hippo...
questionsmedicales.fr › Métabolisme › Métabolisme glucidique › Glycosylation › Protein O-GlcNAcylation coupled to Hippo...