Artículo
Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism
Autor/es | González Rellán, María J.
Fernández, Uxía Parracho, Tamara Novoa, Eva Fondevila, Marcos F. Da Silva Lima, Natalia Rodríguez, Amaia Pérez Mejías, Gonzalo Díaz Quintana, Antonio Jesús Díaz Moreno, Irene Nogueiras, Rubén |
Departamento | Universidad de Sevilla. Departamento de Bioquímica Vegetal y Biología Molecular |
Fecha de publicación | 2023 |
Fecha de depósito | 2023-09-15 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Ministerio de Ciencia, Innovación y Universidades (MICINN). España Xunta de Galicia European Community (EC) |
Identificador del proyecto | PID2020-117116RB-I00
BFU2017-87721 RTI2018-101840-BI00 PID2021-126096NB-I00 RED2018-102379-T 2021-CP085 2020-PG0157 RTC2019-007125-1 DTS20/00138 DTS20/00138 2019-WATCH- 810331 |
Cita | González Rellán, M.J., Fernández, U., Parracho, T., Novoa, E., Fondevila, M.F., Da Silva Lima, N.,...,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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