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 Lopez; Antonio Diaz-Quintana; Carlos Dieguez; Diana Guallar; Gema Frühbeck; Irene Diaz-Moreno; Susana B. Bravo; Maria L. Martinez-Chantar; Ruben Nogueiras

doi:10.1016/j.cmet.2023.07.003

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

Institute of Experimental and Clinical Pharmacology and Toxicology

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 language	English
Journal	Cell Metabolism
Volume	35
Issue number	9
Pages (from-to)	1630-1645.e5
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2023.07.003
Publication status	Published - 05.09.2023

Research Areas and Centers

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

DFG Research Classification Scheme

2.22-09 Pharmacology
2.22-17 Endocrinology, Diabetology, Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2023.07.003

Cite this

Gonzalez-Rellan, M. J., Fernández, U., Parracho, T., Novoa, E., Fondevila, M. F., da Silva Lima, N., Ramos, L., Rodríguez, A., Serrano-Maciá, M., Perez-Mejias, G., Chantada-Vazquez, P., Riobello, C., Veyrat-Durebex, C., Tovar, S., Coppari, R., Woodhoo, A., Schwaninger, M., Prevot, V., Delgado, T. C., ... Nogueiras, R. (2023). Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism. Cell Metabolism, 35(9), 1630-1645.e5. https://doi.org/10.1016/j.cmet.2023.07.003

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title = "Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism",

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.",

author = "Gonzalez-Rellan, {Mar{\'i}a J.} and Ux{\'i}a Fern{\'a}ndez and Tamara Parracho and Eva Novoa and Fondevila, {Marcos F.} and {da Silva Lima}, Natalia and Luc{\'i}a Ramos and Amaia Rodr{\'i}guez and Marina Serrano-Maci{\'a} and Gonzalo Perez-Mejias and Pilar Chantada-Vazquez and Cristina Riobello and Christelle Veyrat-Durebex and Sulay Tovar and Roberto Coppari and Ashwin Woodhoo and Markus Schwaninger and Vincent Prevot and Delgado, {Teresa C.} and Miguel Lopez and Antonio Diaz-Quintana and Carlos Dieguez and Diana Guallar and Gema Fr{\"u}hbeck and Irene Diaz-Moreno and Bravo, {Susana B.} and Martinez-Chantar, {Maria L.} and Ruben Nogueiras",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = sep,

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doi = "10.1016/j.cmet.2023.07.003",

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Gonzalez-Rellan, MJ, Fernández, U, Parracho, T, Novoa, E, Fondevila, MF, da Silva Lima, N, Ramos, L, Rodríguez, A, Serrano-Maciá, M, Perez-Mejias, G, Chantada-Vazquez, P, Riobello, C, Veyrat-Durebex, C, Tovar, S, Coppari, R, Woodhoo, A, Schwaninger, M, Prevot, V, Delgado, TC, Lopez, M, Diaz-Quintana, A, Dieguez, C, Guallar, D, Frühbeck, G, Diaz-Moreno, I, Bravo, SB, Martinez-Chantar, ML & Nogueiras, R 2023, 'Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism', Cell Metabolism, vol. 35, no. 9, pp. 1630-1645.e5. https://doi.org/10.1016/j.cmet.2023.07.003

TY - JOUR

T1 - Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

AU - Gonzalez-Rellan, María J.

AU - Fernández, Uxía

AU - Parracho, Tamara

AU - Novoa, Eva

AU - Fondevila, Marcos F.

AU - da Silva Lima, Natalia

AU - Ramos, Lucía

AU - Rodríguez, Amaia

AU - Serrano-Maciá, Marina

AU - Perez-Mejias, Gonzalo

AU - Chantada-Vazquez, Pilar

AU - Riobello, Cristina

AU - Veyrat-Durebex, Christelle

AU - Tovar, Sulay

AU - Coppari, Roberto

AU - Woodhoo, Ashwin

AU - Schwaninger, Markus

AU - Prevot, Vincent

AU - Delgado, Teresa C.

AU - Lopez, Miguel

AU - Diaz-Quintana, Antonio

AU - Dieguez, Carlos

AU - Guallar, Diana

AU - Frühbeck, Gema

AU - Diaz-Moreno, Irene

AU - Bravo, Susana B.

AU - Martinez-Chantar, Maria L.

AU - Nogueiras, Ruben

PY - 2023/9/5

Y1 - 2023/9/5

N2 - 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.

AB - 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.

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DO - 10.1016/j.cmet.2023.07.003

M3 - Journal articles

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AN - SCOPUS:85169835796

SN - 1550-4131

VL - 35

SP - 1630-1645.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 9

ER -

Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism

Abstract

Research Areas and Centers

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UN SDGs

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