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 | |
| Publication status | Published - 05.09.2023 |
Funding
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.
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
