Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

  • Cell Metab. 2023 Jul 28;S1550-4131(23)00263-2. doi: 10.1016/j.cmet.2023.07.003.
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
Affiliations
  • 1. Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain.
  • 2. Department of Biochemistry, CIMUS, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
  • 3. CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Department of Endocrinology & Nutrition, Metabolic Research Laboratory, Clínica Universidad de Navarra, University of Navarra, IdiSNA, Pamplona, Navarra, Spain.
  • 4. Liver Disease Lab, BRTA CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.
  • 5. Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla-CSIC. Avda. Americo Vespucio 49, 41092 Sevilla, Spain.
  • 6. Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela 15705, A Coruña, Spain.
  • 7. Gene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • 8. Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  • 9. Gene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain.
  • 10. University of Lübeck, Institute for Experimental and Clinical Pharmacology and Toxicology, Lübeck, Germany.
  • 11. University of Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, European Genomic Institute for Diabetes (EGID), 59000 Lille, France.
  • 12. Liver Disease Lab, BRTA CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain. Electronic address: [email protected].
  • 13. Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain. Electronic address: [email protected].
PMID: 37541251 DOI: 10.1016/j.cmet.2023.07.003
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.

Keywords
PCK1; calorie restriction; fasting; glucagon; glucose metabolism; neddylation; type 2 diabetes.
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