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Crotonylation of GAPDH regulates human embryonic stem cell endodermal lineage differentiation and metabolic switch

ABSTRACT: Post-translational modifications of proteins are crucial to the regulation of their activity and function. As a newly discovered acylation modification, crotonylation of non-histone proteins remains largely unexplored, particularly in human embryonic stem cells (hESCs). Here we report the investigation of induced crotonylation in hESCs, which resulted in hESCs of different pluripotency states differentiating into the endodermal lineage. We showed that increased protein crotonylation in hESCs was accompanied by transcriptomic shifts and decreased glycolysis. Through large-scale profiling of non-histone protein crotonylation, we showed that metabolic enzymes were major targets of inducible crotonylation in hESCs. We further discovered GAPDH as a key glycolytic enzyme regulated by crotonylation during endodermal differentiation from hESCs, where crotonylation of GAPDH decreased its enzymatic activity thereby leading to reduced glycolysis. Our study demonstrates that crotonylation of glycolytic enzymes may be crucial to metabolic switching and cell fate determination in hESCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214619 | GEO | 2022/10/03

REPOSITORIES: GEO

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Crotonylation of GAPDH regulates human embryonic stem cell endodermal lineage differentiation and metabolic switch

Project description:Post-translational modifications of proteins are crucial to the regulation of their activity and function. As a newly discovered acylation modification, crotonylation of non-histone proteins remains largely unexplored, particularly in human embryonic stem cells (hESCs). Here we report the investigation of induced crotonylation in hESCs, which resulted in hESCs of different pluripotency states differentiating into the endodermal lineage. We showed that increased protein crotonylation in hESCs was accompanied by transcriptomic shifts and decreased glycolysis. Through large-scale profiling of non-histone protein crotonylation, we identified metabolic enzymes as major targets of inducible crotonylation in hESCs. We further discovered GAPDH as a key glycolytic enzyme regulated by crotonylation during endodermal differentiation from hESCs, where crotonylation of GAPDH decreased its enzymatic activity thereby leading to reduced glycolysis. Our study demonstrates that crotonylation of glycolytic enzymes may be crucial to metabolic switching and cell fate determination in hESCs.

2022-10-27 | PXD027007 | Pride

4-octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

Project description:Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has recently been reported to regulate macrophage function, but its precise mechanism is not fully understood. Here, we showed that 4-octyl itaconate (OI, a cell-permeable itaconate derivative) directly alkylated cysteine residue 22 on the glycolytic enzyme GAPDH and decreased its enzyme activity. Glycolytic flux analysis by U13C‐glucose tracing also provided evidence that OI generated a blockade of glycolytic flux at GAPDH. OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of OI were replicated by heptelidic acid, 2-DG and reversed by increasing wild-type but not C22A mutant GAPDH expression. OI protected against lipopolysaccharide-induced lethality in vivo and significantly inhibited cytokine release. These findings showed that itaconate is a critical immunometabolite that exerts anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

2019-10-02 | MTBLS1140 | MetaboLights

A comprehensive proteome-wide lysine crotonylation profiling of papaya (Carica papaya L.)

Project description:Lysine crotonylation of histone proteins is a recently-identified post-translational modification with multiple cellular functions. However, lysine crotonylation of non-histone proteins in fruit cells has not yet been studied. Using high-resolution LC-MS/MS coupled with highly sensitive immune-affinity antibody analysis, a global crotonylation proteome analysis of papaya (Carica papaya L.) fruit was performed. In total, 2,120 proteins with 5,995 lysine crotonylation sites were discovered, among which eight conserved motifs were identified. Bioinformatic analysis linked crotonylated proteins to multiple metabolic pathways, including biosynthesis of antibiotics, carbon metabolism, biosynthesis of amino acids, and glycolysis. Notably, 40 crotonylated enzymes involved in various amino acid metabolism pathways were identified, suggesting a potential conserved function for crotonylation in the regulation of amino acid metabolism. Numerous crotonylation sites were identified in proteins involved in hormone signaling and cell wall-related pathways, indicating a role for crotonylation in the regulation of fruit ripening in papaya. Our comprehensive crotonylation proteome indicates diverse functions for lysine crotonylation in fruit ripening-related proteins.

2017-12-18 | PXD008166 | Pride

Histone crotonylation

Project description:Histone crotonylation

| PRJNA535529 | ENA

MetaboLights MTBLS1140 - GNPS 4-octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects

Project description:Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has recently been reported to regulate macrophage function, but its precise mechanism is not fully understood. Here, we showed that 4-octyl itaconate (OI, a cell-permeable itaconate derivative) directly alkylated cysteine residue 22 on the glycolytic enzyme GAPDH and decreased its enzyme activity. Glycolytic flux analysis by U13C?glucose tracing also provided evidence that OI generated a blockade of glycolytic flux at GAPDH. OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of OI were replicated by heptelidic acid, 2-DG and reversed by increasing wild-type but not C22A mutant GAPDH expression. OI protected against lipopolysaccharide-induced lethality in vivo and significantly inhibited cytokine release. These findings showed that itaconate is a critical immunometabolite that exerts anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.

2020-07-22 | MSV000085812 | GNPS

GAPDH interactome in micelium to yeast transition Paracoccidioides lutzii cells

Project description:we show an overview of experimental GAPDH interactome in different phases of P. lutzii. Several proteins bound to GAPDH from mycelium, transition and yeast are common to important pathways such as glycolysis and TCA.

2019-07-29 | PXD008317 | Pride

DIA proteomics on mouse tissue to investigate the GAPDH redox switch

Project description:The glycolytic enzyme GAPDH is equipped with a redox switch that rapidly and reversibly inactivates the enzyme in the presence of hydrogen peroxide. The physiological implications of the redox switch were investigated in C57BL/6NTac wildtype and GAPDH(T175A) knock-in mice generated by CRISPR/Cas9 genome editing.

2023-04-10 | PXD040620 | Pride

Protein-protein interactions overview of the moonlighting protein GAPDH in Paracoccidioides lutzii

Project description:we show an overview of experimental GAPDH interactome in different phases of P. lutzii and GAPDH interactions with macrophage proteins. Several proteins bound to GAPDH from mycelium, transition and yeast are common to important pathways such as glycolysis and TCA.

2019-07-29 | PXD008253 | Pride

Genome-wide profiling of histone lysine crotonylation reveals positive regulation of transcription in rice

Project description:Histone lysine crotonylation (Kcr) is a newly discovered post-translational modification (PTM) existing in mammalian. To assess relevance in histone Kcr and genome, we performed on genomic localization analysis of histone Kcr by ChIP-seq analysis.

2018-06-01 | GSE108542 | GEO

Defining the mechanisms and consequences of glycolytic metabolism in human pluripotent stem cells

Project description:The balance between glycolytic and oxidative metabolism shifts during differentiation of human embryonic stem cells (hESCs) and during reprogramming of somatic cells into pluripotent stem cells. However the contribution of glycolytic metabolism to various stages of pluripotency is not well understood. Additionally, few tools have been developed that modulate pluripotent stem cell glycolytic metabolism to influence self-renewal or differentiation. Here we show that the degree of human pluripotency is associated with glycolytic rate, whereby naive hESCs exhibit higher glycolytic flux, increased MYC transcriptional activity, and elevated nuclear N-MYC levels relative to primed hESCs. Consistently, the inner cell mass of human blastocysts also exhibits increased MYC transcriptional activity relative to primed hESCs and elevated nuclear N-MYC levels. Expression of the lactate transporter, monocarboxylate transporter 1 (MCT1), is strongly associated with the pluripotent state, and reduction of glycolysis using a small molecule inhibitor towards MCT1 decreases self-renewal of naïve hESCs and feeder-free cultured primed hESCs, but not that of primed hESCs grown in feeder-supported conditions. Lastly, reduction of glycolytic metabolism via MCT1 inhibition in feeder-free primed hESCs enhances neural lineage specification. These findings validate the association between glycolytic metabolism and pluripotency, reveal differences in the glucose metabolism of feeder- versus feeder-free cultured hESCs, and show that pharmacologic regulation of glycolysis can influence self-renewal and initial cell fate specification of human pluripotent stem cells.

2016-08-16 | GSE83491 | GEO

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