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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation

ABSTRACT: Metabolite-coupled post-translation modifications (PTMs) plays a crucial role in the regulation of gene expression and protein functions. In this study, we present the identification and characterization of a novel protein modification, named lysine pyruvatylation (Kpy). We identified five pyruvatylation sites on core histones and 68 sites on non-histone proteins in mammal cells. The levels of Kpy can be increased by adding sodium pyruvate and are influenced by changes in the glycolytic pathway. Through a screening of potential enzymes, we identified SIRT3 as the “eraser” of Kpy, while HAT1 and p300 function as the “writers”. Collectively, this study uncovers a new type of PTM, pyruvatylation, which is derived from pyruvate, and reveals the key regulatory elements for the Kpy pathway, laying a foundation for studying its roles in diverse cellular processes.

ORGANISM(S): Homo Sapiens

SUBMITTER: He Huang

PROVIDER: PXD072283 | iProX | Sun Dec 21 00:00:00 GMT 2025

REPOSITORIES: iProX

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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation

Project description:Post-translational modifications (PTMs) serve as critical regulatory mechanisms connecting metabolism and protein functions. Following our prior discovery of lysine lactylation (Kla), we herein report the identification and characterization of lysine pyruvylation (Kpy), a previously undescribed PTM driven by the central glycolytic hub metabolite pyruvate. Through integrated biochemical and proteomic strategies, we established the existence and specificity of Kpy. Proteomic profiling revealed Kpy sites across both histones and non-histone proteins, implicating its broad physiological significance. Notably, our investigations demonstrated that Kpy abundance fluctuates in respond to alterations in glycolytic flux and pyruvate concentration, providing a direct mechanism by which metabolic alterations influence protein functions. Additionally, we identified Sirtuin 3 (SIRT3) as the "eraser" enzyme for Kpy removal, while Histone acetyltransferase 1 (HAT1) and p300 (EP300) function as "writer" enzymes responsible for Kpy deposition. Initial mechanistic studies suggested Kpy's regulatory role in transcriptional control. Together, the elucidation of Kpy expands our understanding of metabolite-protein crosstalk through PTMs, providing mechanistic insights into pathophysiological processes and facilitating the development of targeted therapeutic interventions for metabolic disorders.

2025-04-23 | GSE295067 | GEO

Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation [RNA-seq]

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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation [RNA-Seq]

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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation

Project description:Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation

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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation [RNA-Seq]

Project description:Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation [RNA-Seq]

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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation [CUT&Tag]

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Lysine Pyruvylation Mediated by HAT1/p300-SIRT3 Couples Glycolytic Flux to Epigenetic Regulation [RNA-seq]

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SIRT1/SIRT3 are robust lysine delactylases and SIRT1-mediated delactylation regulates glycolysis

Project description:Lysine lactylation (Kla), a newly identified epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, marks a pivotal juncture between metabolic pathways and gene regulation. The discovery of enzymes such as p300 and HDAC1/3 has been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Our investigation bridges these knowledge gaps by identifying SIRT1 and SIRT3 as key "erasers" of Kla, providing insights into their selective regulatory impact on both histone and non-histone proteins. Through a quantitative proteomic analysis in wildtype, SIRT1 knockout, and SIRT3 knockout HepG2 cells, we delineated a comprehensive landscape of Kla and lysine acetylation (Kac) sites. The results demonstrate a distinct specificity in the substrates modified by SIRT1 and SIRT3, underscoring their differentiated roles in cellular signaling pathways. Particularly, we highlight the role of specific Kla modifications, such as those on the M2 splice isoform of pyruvate kinase (PKM2), in modulating metabolic pathways and cell proliferation, thereby expanding the recognized implications of Kla beyond its epigenetic roles. Therefore, this study paves the way for deeper understanding of the functional phenotypes and mechanisms of Kla, offering new insights into its broader biological significance.

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SIRT3 functions in the nucleus in the control of stress-related gene expression.

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2012-10-16 | E-GEOD-41000 | biostudies-arrayexpress

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