Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism
Keywords: 
PCK1
Calorie restriction
Fasting
Glucagon
Glucose metabolism
Neddylation
Type 2 diabetes
Issue Date: 
2023
Publisher: 
Elsevier
Project: 
info:eu-repo/grantAgreement/AEI/Proyectos I+D/PID2020-117116RB-I00/[ES]/DESVELANDO EL PAPEL DE LA NEDILACION EN EL ESTRES NUTRICIONAL
ISSN: 
1932-7420
Note: 
This is an open access article under the CC BY-NC-ND license
Citation: 
Gonzalez-Rellan, M.J. (María J.); Fernández, U. (Uxía); Parracho, T. (Tamara); et al. "Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism". Cell Metabolism. 35 (9), 2023, 1630 - 1645
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.

Files in This Item:
Thumbnail
File
PIIS1550413123002632.pdf
Description
Size
7.11 MB
Format
Adobe PDF


Statistics and impact
0 citas en
0 citas en

Items in Dadun are protected by copyright, with all rights reserved, unless otherwise indicated.