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^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie

35 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Cell Metabolism
Jahrgang	35
Ausgabenummer	9
Seiten (von - bis)	1630-1645.e5
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2023.07.003
Publikationsstatus	Veröffentlicht - 05.09.2023

Fördermittel

This work was supported by grants from: FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (M.L.M.-C.: PID2020-117116RB-I00; C.D.: BFU2017-87721; M.L.: RTI2018-101840-B-I00; R.N.: PID2021-126096NB-I00 and RED2018-102379-T); Xunta de Galicia (R.N.: 2021-CP085 and 2020-PG0157); Fundación BBVA (to R.N.); Subprograma Retos Colaboración RTC2019-007125-1 (to M.L.M.-C.); Proyectos Investigación en Salud DTS20/00138 (to M.L.M.-C.); Proyectos Investigación en Salud (M.L.M.-C.: DTS20/00138); Fundación Atresmedia (to M.L. and R.N.); and Fundación La Caixa (to M.L. M.L.M.-C. and R.N.). This research also received funding from the European Community's H2020 Framework Programme (ERC Synergy Grant-2019-WATCH- 810331, to R.N. V.P. and M.S.). The Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and the Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd) are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation bioGUNE (SEV-2016-0644) to CIC. M.J.G.-R. and U.F. conceived the study, designed and conducted experiments, analyzed results, and contributed to the manuscript preparation. T.P. E.N. M.F.F. N.d.S.L. L.R. A.R. M.S.-M. G.P.-M. P.C.-V. C.R. C.V.-D. S.T. R.C. A.W. M.S. V.P. T.C. D, M.L. A.D.-Q. C.D. D.G. G.F. I.D.-M. and S.B.B. contributed to the performance of experiments and to the manuscript preparation. M.L.M.-C. and R.N. conceived the study; designed, coordinated, and supervised experiments; wrote the manuscript; and secured funding. All authors discussed the results, commented on the manuscript before submission, and agreed with the final submitted manuscript. The authors declare no competing interests. This work was supported by grants from: FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (M.L.M.-C.: PID2020-117116RB-I00 ; C.D.: BFU2017-87721 ; M.L.: RTI2018-101840-B-I00 ; R.N.: PID2021-126096NB-I00 and RED2018-102379-T ); Xunta de Galicia (R.N.: 2021-CP085 and 2020-PG0157 ); Fundación BBVA (to R.N.); Subprograma Retos Colaboración RTC2019-007125-1 (to M.L.M.-C.); Proyectos Investigación en Salud DTS20/00138 (to M.L.M.-C.); Proyectos Investigación en Salud (M.L.M.-C.: DTS20/00138 ); Fundación Atresmedia (to M.L. and R.N.); and Fundación La Caixa (to M.L., M.L.M.-C., and R.N.). This research also received funding from the European Community’s H2020 Framework Programme (ERC Synergy Grant-2019-WATCH- 810331 , to R.N., V.P., and M.S.). The Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and the Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd) are initiatives of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. We thank MINECO for the Severo Ochoa Excellence Accreditation bioGUNE ( SEV-2016-0644 ) to CIC.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

DFG-Fachsystematik

2.22-09 Pharmakologie
2.22-17 Endokrinologie, Diabetologie, Metabolismus

Dokumente

10.1016/j.cmet.2023.07.003

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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

@article{050390ad835d47d0940e7a1ab1aba162,

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,

day = "5",

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

language = "English",

volume = "35",

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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, Jg. 35, Nr. 9, S. 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.

UR - https://www.scopus.com/pages/publications/85169835796

UR - https://www.mendeley.com/catalogue/65965e72-4926-307e-bbf1-f2e3ee97d59e/

U2 - 10.1016/j.cmet.2023.07.003

DO - 10.1016/j.cmet.2023.07.003

M3 - Journal articles

C2 - 37541251

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

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