Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.
Cell Metab
; 35(9): 1630-1645.e5, 2023 09 05.
Article
em En
| MEDLINE
| ID: mdl-37541251
ABSTRACT
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
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Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 2
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article