Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain.
Department of Biochemistry, CIMUS, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
Cell Metab. 2023 Sep 5;35(9):1630-1645.e5. doi: 10.1016/j.cmet.2023.07.003. Epub 2023 Aug 3.
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.
类泛素化是一种在翻译后修饰蛋白质的机制，它可以给蛋白质添加一个类泛素样蛋白，即神经前体细胞表达发育下调蛋白 8（NEDD8）。在这里，我们展示了营养物质供应对小鼠肝脏中类泛素化的调节作用。在小鼠肝脏中抑制类泛素化会降低糖异生能力和抗胰岛素激素的升血糖作用。此外，2 型糖尿病患者的肝内类泛素化水平升高。从机制上讲，禁食或热量限制会导致磷酸烯醇丙酮酸羧激酶 1（PCK1）在三个赖氨酸残基-K278、K342 和 K387 处发生类泛素化。我们发现，突变三个发生类泛素化的 PCK1 赖氨酸会降低其糖异生活性。分子动力学模拟表明，PCK1 的类泛素化可以将围绕催化中心的两个环重新定位到开放构象，从而使催化中心更容易接近。我们的研究揭示了 PCK1 的类泛素化通过将整体营养物质可用性与代谢稳态联系起来，为控制葡萄糖代谢提供了一种精细调节的机制。
