Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

María J. Gonzalez-Rellan, Uxía Fernández, Tamara Parracho, Eva Novoa, Marcos F. Fondevila, Natalia da Silva Lima, Lucía Ramos, Amaia Rodríguez, Marina Serrano-Maciá, Gonzalo Perez-Mejias, Pilar Chantada-Vazquez, Cristina Riobello, Christelle Veyrat-Durebex, Sulay Tovar, Roberto Coppari, Ashwin Woodhoo, Markus Schwaninger, Vincent Prevot, Teresa C. Delgado, Miguel LopezAntonio Diaz-Quintana, Carlos Dieguez, Diana Guallar, Gema Frühbeck, Irene Diaz-Moreno, Susana B. Bravo, Maria L. Martinez-Chantar*, Ruben Nogueiras*

*Corresponding author for this work

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.

Original languageEnglish
JournalCell Metabolism
Volume35
Issue number9
Pages (from-to)1630-1645.e5
ISSN1550-4131
DOIs
Publication statusPublished - 05.09.2023

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

  • 205-09 Pharmacology
  • 205-17 Endocrinology, Diabetology, Metabolism

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