Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism
María J. Gonzalez-Rellan, Uxía Fernández, Tamara Parracho, Eva Nóvoa, Marcos F. Fondevila, Natália da Silva Lima, Lucía Ramos, Amaia Rodrı́guez, Marina Serrano‐Maciá, Gonzalo Pérez‐Mejías, Pilar Chantada-Vazquez, Cristina Riobello, Christelle Veyrat‐Durebex, Sulay Tovar, Roberto Coppari, Ashwin Woodhoo, Markus Schwaninger, Vincent Prévot, Teresa C. Delgado, Miguel López, Antonio Dı́az-Quintana, Carlos Diéguez, Diana Guallar, Gema Frühbeck, Irene Díaz‐Moreno, Susana B. Bravo, Maria Luz Martínez‐Chantar, Rubén Nogueiras
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.