| First Author | Gonzalez-Rellan MJ | Year | 2023 |
| Journal | Cell Metab | Volume | 35 |
| Issue | 9 | Pages | 1630-1645.e5 |
| PubMed ID | 37541251 | Mgi Jnum | J:341128 |
| Mgi Id | MGI:7528555 | Doi | 10.1016/j.cmet.2023.07.003 |
| Citation | Gonzalez-Rellan MJ, et al. (2023) Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism. Cell Metab 35(9):1630-1645.e5 |
| abstractText | 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. |
