Lysine Methylpropionylation, a Hybrid Post-Translational Modification Mediated by p300/PCAF Couples Metabolic Dynamics with Protein Function
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE295019 | GEO | 2025/04/30
REPOSITORIES: GEO
Similar Datasets
Project description:Lysine alkylation and acylation serve as crucial links between cellular metabolism and a wide range of biological functions. However, hybrid modifications that combine features of both alkylation and acylation remain largely unexplored. Here, we report the discovery and in-depth characterization of lysine methylpropionylation (Kpm), a hybrid post-translational modification (PTM) defined by the propionylation of monomethyllysine residues. Mechanistically, we show that Kpm is metabolically regulated by propionyl-CoA homeostasis and is markedly upregulated upon depletion of the propionyl-CoA carboxylase beta subunit (PCCB). Genome-wide chromatin immunoprecipitation coupled with transcriptomic profiling revealed that Kpm exhibits distinct genomic distribution compared to canonical Kac and Kpr, with preferential enrichment at promoters of genes involved in metabolic pathways. To investigate the site-specific function of Kpm on non-histone proteins, we developed a genetic code expansion system to incorporate Kpm at defined sites. Using this system, we demonstrate that methylpropionylation of NSMCE3 at lysine 260 disrupts a critical electrostatic interaction with E284, thereby impairing its association with NSMCE4A and compromising DNA damage repair. Together, our findings establish Kpm as a dual-feature PTM that integrates metabolic cues with both chromatin regulation and non-histone protein function, offering a mechanistic framework for understanding metabolism-proteome crosstalk.
2025-04-20 | GSE294818 | GEO
Project description:We report the identification of 67 previously undescribed histone modifications, increasing the current number of known histone marks by about 70%. We further investigated one of the marks, lysine crotonylation (Kcr), confirming that it represents an evolutionarily-conserved histone posttranslational modification. The unique structure and genomic localization of histone Kcr suggest that it is mechanistically and functionally different from histone lysine acetylation (Kac). Specifically, in both human somatic and mouse male germ cell genomes, histone Kcr marks either active promoters or potential enhancers. In male germinal cells immediately following meiosis, Kcr is enriched on sex chromosomes and specifically marks testis-specific genes, including a significant proportion of X-linked genes that escape sex chromosome inactivation in haploid cells. These results therefore dramatically extend the repertoire of histone PTM sites and designate Kcr as a specific mark of active sex chromosome-linked genes in postmeiotic male germ cells. 2 histone marks (pan-lysine acetylation and pan-lysine crotonylation) were studied in 1 human cell type and 2 mouse cell types using ChIP-Seq. Input was sequenced for each cell type as a control. Pan-anti_Kac and pan-anti_Kcr antibodies were custom developed with PTM BioLab, Co., Ltd (Chicago, IL).
2011-10-06 | E-GEOD-32663 | biostudies-arrayexpress
Project description:Lysine Methylpropionylation, a Hybrid Post-Translational Modification Mediated by p300/PCAF Couples Metabolic Dynamics with Protein Function
| PRJNA1252466 | ENA
Project description:Lysine-epsilon-acetylation (Kac) is a post-translational modification (PTM) that is critical for metabolic regulation and cell signaling in mammals. Here, proteins were extracted from five representative Arabidopsis organs and digested by trypsin, and the acetylated peptides were enriched by anti-acetyllysine antibody. The enriched peptides were analyzed using LC-MS/MS.
2021-11-25 | MSV000088454 | MassIVE
Project description:Cholesterol of the host macrophage membrane is vital for mycobacterial infection, replication, and persistence. During chronic infection within host lung tissues, cholesterol facilitates the phagocytosis of mycobacteria into macrophages. Cholesterol degradation leads to increased flux of acetyl-coenzyme A (CoA) and propionyl-CoA, providing energy and building blocks for virulence macromolecules as well as donors for global protein acylation. Potential functions of lysine acylation are gradually revealed in bacterial survival and pathogenesis. However, the mycobacterial proteome and posttranslational modification (PTM) changes involved in the cholesterol catabolism bioprocess remain unclear. Here, we used nonpathogenic Mycobacterium smegmatis as a model and simultaneously monitored mycobacterial proteome and acetylome changes in the presence of glucose and cholesterol. We discovered that cholesterol metabolic enzymes were upregulated with respect to both protein expression levels and lysine acylation levels during the metabolic shift from glucose to cholesterol. After that, adenylating enzymes related to cholesterol metabolism were proven to be precisely regulated at the propionylation level by mycobacterial acyltransferase M. smegmatis Kat (MsKat) in response to cellular propionyl-CoA accumulation. Furthermore, the kinase expression and phosphorylation levels were also changed along with fluctuations in cholesterol levels. Our results expanded current knowledge of acylation regulation in the cholesterol catabolism of mycobacteria and provided references for possible antimycobacterium strategy.IMPORTANCE Cholesterol assimilation is a critical step in mycobacterial chronic infection. However, knowledge from the dynamic characterization of cholesterol metabolism in mycobacteria at the protein expression and PTM levels remains limited. Our study uncovered the landscape of protein expression, lysine acetylation, lysine propionylation, and S/T/Y phosphorylation during the metabolic changes from glucose to cholesterol in mycobacteria. The data showed that cholesterol-induced carbon shift resulted in the elevation of protein expression and lysine acylation in diverse metabolic enzymes involved in cholesterol degradation and that the presence of cholesterol also promoted the perturbations at the phosphorylation level in the kinase system in mycobacteria. This study systematically characterized the regulation of cholesterol catabolism at several different levels, which provided the detailed references in mycobacterial proteome and potential antimycobacterial strategies.
2019-12-03 | PXD014366 |
Project description:Daphnia (Daphnia pulex) is a small planktonic crustacean and a key constituent of aquatic ecosystems. It is commonly used as a model organism for studying environmental toxic challenges. In the past decade, a Daphnia genomic information and proteomic dataset has been developed. This dataset has expanded the opportunity to relate toxicological effects with “Daphnia proteomics” as it integrates proteomic knowledge in Daphnia, those approach will provide greater insights for toxicological research. In order to exploit Daphnia for ecotoxicological research, information on the post-translational modification (PTM) of proteins is necessary as this is a critical regulator of biological processes. Acetylation of lysine (Kac) is a reversible and highly regulated PTM that is associated with diverse biological functions. However, a comprehensive description of Kac in Daphnia is not yet available. Here, to understand the cellular distribution of lysine acetylation in Daphnia, we identified 98 acetylation sites in 65 proteins by immunoprecipitation using an anti-acetyllysine antibody and an liquid chromatography system supported by mass spectroscopy. We identified 28 acetylated sites connected with metabolic proteins and 6 acetylated enzymes associated with the TCA cycle in Daphnia. From GO and KEGG enrichment analyses, we showed that Kac in D. pulex is highly enriched in proteins associated with metabolic processes. Our data provide the first global analysis of lysine acetylation in D. pulex. The expanded proteomic dataset will be an important resource for the functional analysis of Kac in D. pulex and it will be nice to have a first step done using a promising future model organism.
2016-01-05 | PXD002441 | Pride
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
Project description:Kac, a reversible PTM, plays essential roles in various biological processes, including those involving metabolic pathways, pathogen resistance and transcription, in both prokaryotes and eukaryotes. TMV, the major factor that causes poor quality of Solanaceae crops worldwide, directly alters many metabolic processes in tobacco. However, the extent and function of Kac during TMV infection have not been determined. Here, using LC−MS/MS in conjunction with highly sensitive immune-affinity purification, we comprehensively analyzed the changes in the proteome and acetylome of TMV-infected tobacco (Nicotiana benthamiana) seedlings. In total, 2082 lysine-acetylated sites on 1319 proteins differentially expressed in response to TMV infection were identified. Extensive bioinformatic studies disclosed changes in acetylation of proteins engaged in cellular metabolism and biological processes. The vital influence of Kac in fatty acid degradation and alpha-linolenic acid metabolism was also revealed in TMV-infected seedlings. This study first revealed Kac information in N. benthamiana under TMV infection and expands upon the existing landscape of acetylation in pathogen infection.
2022-10-15 | PXD035737 | Pride
Project description:Campylobacter jejuni is the leading cause of acute bacterial gastroenteritis in the developed world. Despite the prevalence of infection, the pathogenesis of C. jejuni remains poorly understood. Lysine acetylation (KAc) is a reversible post-translational modification (PTM) that can alter the protein structure / function paradigm, however specific roles for KAc are largely undefined in bacteria. Acetyl-lysine immunoprecipitation and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) identified 5567 acetylated lysines on 1026 C. jejuni proteins (~63% of the predicted C. jejuni proteome). Functional enrichment confirmed acetylated proteins are involved in metabolism, transcription and translation, stress responses and chemotaxis. KAc was identified on proteins from all subcellular locations, including outer membrane (OM) and extracellular proteins. Label-based LC-MS/MS identified acetylated proteins and modified sites associated with growth in 0.1% sodium deoxycholate (DOC, a component of gut bile salts). A total of 3571 acetylated peptides were quantified and 761 (from 409 proteins) were differentially abundant following growth in DOC. Changes in KAc involved multiple pathways suggesting a dynamic role for this PTM in bile resistance. As observed in other bacteria, we show that KAc is primarily non-enzymatically mediated via acetyl-phosphate; however, the sole deacetylase CobB also contributes to a global elevation of this modification in DOC. We observed several multiply acetylated OM proteins and altered DOC abundance of acetylated peptides in the major fibronectin (Fn)-binding adhesin CadF. We show that KAc influences CadF Fn binding and prevalence of processed lower mass variants. This study provides the first system-wide analysis of the C. jejuni lysine acetylome and contributes to our understanding of KAc as an emerging PTM in bacteria.
2025-03-11 | PXD042815 | Pride
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.
2025-04-24 | GSE295252 | GEO