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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.

SUBMITTER: Gonzalez-Rellan MJ

PROVIDER: S-EPMC10487638 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.

Gonzalez-Rellan María J MJ Fernández Uxía U Parracho Tamara T Novoa Eva E Fondevila Marcos F MF da Silva Lima Natalia N Ramos Lucía L Rodríguez Amaia A Serrano-Maciá Marina M Perez-Mejias Gonzalo G Chantada-Vazquez Pilar P Riobello Cristina C Veyrat-Durebex Christelle C Tovar Sulay S Coppari Roberto R Woodhoo Ashwin A Schwaninger Markus M Prevot Vincent V Delgado Teresa C TC Lopez Miguel M Diaz-Quintana Antonio A Dieguez Carlos C Guallar Diana D Frühbeck Gema G Diaz-Moreno Irene I Bravo Susana B SB Martinez-Chantar Maria L ML Nogueiras Ruben R

Cell metabolism 20230803 9

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 ...[more]

PMID: 37541251

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Project description:ObjectivesThyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation.MethodsRNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human β-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR.ResultsWe found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPβ) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human β-cells. In β-cells, T3 and glucose coordinately regulate the expression of ChREBPβ and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for β-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human β-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased β-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPβ contributes to Pck1-dependent β-cell proliferation in mouse β-cells.ConclusionsWe conclude that T3 and glucose act together to regulate ChREBPβ, leading to increased expression and activity of Pck1, and ultimately increased β-cell proliferation.

Dataset Information

Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.

Publications

Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.

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