DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic ß cell function upon overnutrition.
Sci Transl Med
; 16(733): eade8647, 2024 Feb 07.
Article
em En
| MEDLINE
| ID: mdl-38324636
ABSTRACT
Impeded autophagy can impair pancreatic ß cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic ß cells protected ß cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51-like autophagy activating kinase 1 (ULK1) at Ser56, which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic ß cells upon metabolic challenge, which offers a potential target to protect ß cell function in T2D.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
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Hipernutrição
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Diabetes Mellitus Tipo 2
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Células Secretoras de Insulina
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Proteínas Reguladoras de Apoptose
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Proteína Homóloga à Proteína-1 Relacionada à Autofagia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Transl Med
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article