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  3. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

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

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: mlmartinez@cicbiogune.es.
  • 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: ruben.nogueiras@usc.es.
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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