Lysine acetylations in Staphylococcus aureus
Ontology highlight
ABSTRACT:
ORGANISM(S): Staphylococcus Aureus
SUBMITTER: 
Junyu Xu
PROVIDER: PXD057774 | iProX | Tue Nov 12 00:00:00 GMT 2024
REPOSITORIES: iProX
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Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-03-05 | GSE226139 | GEO
Project description:Protein acylation links energetic substrate flux with cellular adaptive responses. SIRT5 is a NAD+-dependent lysine deacylase and removes both succinyl and malonyl group. Using affinity enrichment and label free quantitative proteomics, we characterized the SIRT5-regulated lysine malonylome in wild type (WT) and Sirt5-/- mice. 1137 malonyllysine sites were identified across 430 proteins, with 183 sites (from 120 proteins) significantly increased in the Sirt5-/- animals. Pathway analysis identified glycolysis as the top SIRT5-regulated pathway. Importantly, glycolytic flux was diminished in primary hepatocytes from Sirt5-/- compared to WT mice. Substitution of malonylated lysine residue 184 in glyceraldehyde 3-phosphate dehydrogenase with glutamic acid, a malonyllysine mimic, suppressed its enzymatic activity. Comparison of our previous reports on acylation reveals that malonylation targets a different set of proteins than acetylation and succinylation. These data demonstrate that SIRT5 is a global regulator of lysine malonylation and provide a mechanism for regulation of energetic flux through glycolysis.
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Project description:Cancer cells undergo metabolic reprogramming that is intricately linked to malignancy. Protein acylation is especially responsive to metabolic changes, influencing signal transduction pathways and fostering cell proliferation. However, the role of malonylation in cancer remains poorly understood. In this study, Subsequent nucleic malonylome analysis revealed 99 malonylation sites in 52 proteins within HCC cells.
2025-05-06 | PXD048727 | Pride
Project description:Post-translational modifications (PTMs) are critical regulators of bacterial biofilm formation, but the role of lysine malonylation (Kmal) in biofilm formation is still poorly understood. In this study, we analyzed the dynamic changes of protein malonylation of Staphylococcus aureus (S. aureus) DC15 during biofilm formation based on antibody affinity enrichment combined with quantitative proteomics. Quantitative profiling identified 2,833 malonylated sites across 788 proteins, with significant enrichment in biofilm-associated proteins. Twelve conserved motifs, including Kmal******R and Kmal****R (* represents any amino acid residue), dominated the malonyl proteome landscape in S. aureus. The combined analysis of modified and quantitative proteomics revealed the quorum-sensing system as a key regulatory hub in S. aureus biofilm formation. In particular, the response regulator, AgrA, showed decreased expression but increased malonylation at the K2, K11 and K216 sites during S. aureus biofilm formation, suggesting functional compensation. Structural and phylogenetic analysis showed that the key malonylation sites (K216) of protein AgrA were evolutionarily conserved in Gram-positive pathogens including Bacillus cereus. Molecular docking analysis found that antimicrobial peptide BCp12 and natural compound chlorogenic acid could bind with the malonylation sites in AgrA (ΔG = 6.888 and 5.302 kcal/mol, respectively). This study provides a new perspective for understanding the general rules of bacterial biofilm formation and developing broad-spectrum anti-biofilm drugs.
2025-07-21 | PXD066374 |
Project description:Post-translational modifications (PTMs) are critical regulators of bacterial biofilm formation, but the role of lysine malonylation (Kmal) in biofilm formation is still poorly understood. In this study, we analyzed the dynamic changes of protein malonylation of Staphylococcus aureus (S. aureus) DC15 during biofilm formation based on antibody affinity enrichment combined with quantitative proteomics. Quantitative profiling identified 2,833 malonylated sites across 788 proteins, with significant enrichment in biofilm-associated proteins. Twelve conserved motifs, including Kmal******R and Kmal****R (* represents any amino acid residue), dominated the malonyl proteome landscape in S. aureus. The combined analysis of modified and quantitative proteomics revealed the quorum-sensing system as a key regulatory hub in S. aureus biofilm formation. In particular, the response regulator, AgrA, showed decreased expression but increased malonylation at the K2, K11 and K216 sites during S. aureus biofilm formation, suggesting functional compensation. Structural and phylogenetic analysis showed that the key malonylation sites (K216) of protein AgrA were evolutionarily conserved in Gram-positive pathogens including Bacillus cereus. Molecular docking analysis found that antimicrobial peptide BCp12 and natural compound chlorogenic acid could bind with the malonylation sites in AgrA (ΔG = 6.888 and 5.302 kcal/mol, respectively). This study provides a new perspective for understanding the general rules of bacterial biofilm formation and developing broad-spectrum anti-biofilm drugs.
2025-07-21 | PXD066349 |
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.
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Project description:Background: Sanghuangporus sanghuang is a well-known traditional medicinal mushroom associated with mulberry, which has enormous economic and medical value. Despite being known for many years, the regulatory mechanisms of bioactive compounds biosynthesis in this medicinal mushroom are still unclear.Lysine malonylation is one of a post-translational modifications that has many critical functions in various aspects of cell metabolism. However, at present we do not know its role in S. sanghuang. In this study, a global investigation of lysine malonylome in S. sanghuang was therefore carried out. Results: In total, 714 malonyl modification sites were matched to 255 different proteins. The analysis indicated that malonyl modifications were involved in a wide range of acellular functions and displayed a distinct subcellular localization. Bioinformatics analysis indicated that malonylated proteins were engaged in different metabolic pathways, including glyoxylate and dicarboxylate metabolism, glycolysis/gluconeogenesis, and the tricarboxylic acid (TCA) cycle. Notably, a total of 26 enzymes related to triterpene and polysaccharide biosynthesis were found to be malonylated, indicating an indispensable role of lysine malonylation in bioactive compounds biosynthesis in S. sanghuang. Conclusions: These findings suggest that malonylation is associated with many metabolic pathways, particularly the metabolism of bioactive compounds triterpene and polysaccharide. This paper represents the first comprehensive survey of malonylation in S. sanghuang and provides an important data for further study on the physiological function of lysine malonylation in S. sanghuang and other medicinal mushrooms.
2022-02-17 | PXD025835 | Pride
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-07-21 | PXD040481 | Pride
Project description:TEAD transcription factors are responsible for the transcriptional output of Hippo signalling1,2. TEAD activity is primarily regulated by phosphorylation of its coactivators YAP and TAZ3,4. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity5,6. Here, we report lysine long-chain fatty acylation as a novel posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a “stable active form”. Significantly, lysine fatty acylation of TEAD increased upon Hippo signalling activation, despite a decrease in cysteine acylation. Our results provide new insight into the role of fatty acyl modifications in the regulation of TEAD activity.
2023-03-19 | PXD033939 | Pride
Project description:Toxoplasma gondii is a protozoan parasite which can infect a wide range of animals, including humans. According to virulence, it is generally divided into three different strains, namely type I (RH strain), type II (PRU strain) and type III (VEG strain). Lysine malonylation (Kmal) is a new type of post-translational modification (PTM), which has been reported to regulate diverse biological pathways in various organisms, including T. gondii. However, there is no knowledge about whether lysine malonylation regulates the virulence of different strains in T. gondii. In this study, for the first time, we identified and quantified lysine malonylation level in three strains of T. gondii. In total, 111 proteins and 152 sites were up-regulated, 17 proteins and sites were down-regulated in RH compared with PRU strains, respectively; 50 proteins and 59 sites were up-regulated, 50 proteins and 53 sites were down-regulated in RH strain compared with VEG strains; 72 proteins and 90 sites were up-regulated, 7 proteins and 8 sites were down-regulated in VEG strain compared with PRU strains. Further analysis indicates that these proteins are involved in many important biological processes and regulating virulence-related functions of T. gondii. These findings provide novel and important resource for the role of lysine malonytion in virulence of T. gondii and provide a new direction for the research of vaccine in T. gondii.
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