Scientific publications
Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism. Scientific Publication
María J Gonzalez-Rellan 1 , Uxía Fernández 1 , Tamara Parracho 1 , Eva Novoa 1 , Marcos F Fondevila 1 , Natalia da Silva Lima 1 , Lucía Ramos 2 , Amaia Rodríguez 3 , Marina Serrano-Maciá 4 , Gonzalo Perez-Mejias 5 , Pilar Chantada-Vazquez 6 , Cristina Riobello 7 , Christelle Veyrat-Durebex 8 , Sulay Tovar 1 , Roberto Coppari 8 , Ashwin Woodhoo 9 , Markus Schwaninger 10 , Vincent Prevot 11 , Teresa C Delgado 4 , Miguel Lopez 1 , Antonio Diaz-Quintana 5 , Carlos Dieguez 1 , Diana Guallar 2 , Gema Frühbeck 3 , Irene Diaz-Moreno 5 , Susana B Bravo 6 , Maria L Martinez-Chantar 12 , Ruben Nogueiras 13
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.
CITATION Cell Metab. 2023 Sep 5;35(9):1630-1645.e5. doi: 10.1016/j.cmet.2023.07.003. Epub 2023 Aug 3
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