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British Journal of Pharmacology Jan 2021Epigenetic mechanisms, including DNA methylation and histone post-translational modifications (PTMs), have been known to regulate chromatin structure and... (Review)
Review
Epigenetic mechanisms, including DNA methylation and histone post-translational modifications (PTMs), have been known to regulate chromatin structure and lineage-specific gene expression during cardiovascular development and disease. However, alterations in the landscape of histone PTMs and their contribution to the pathogenesis of incurable cardiovascular diseases such as pulmonary hypertension (PH) and associated right heart failure (RHF) remain largely unexplored. This review focusses on the studies in PH and RHF that investigated the gene families that write (histone acetyltransferases), read (bromodomain-containing proteins) or erase (histone deacetylases [HDACs] and sirtuins [SIRT]) acetyl moieties from the ε-amino group of lysine residues of histones and non-histone proteins. Analysis of cells and tissues isolated from the in vivo preclinical models of PH and human pulmonary arterial hypertension not only confirmed significant alterations in the expression levels of multiple HDACs, SIRT1, SIRT3 and BRD4 proteins but also demonstrated their strong association to proliferative, inflammatory and fibrotic phenotypes linked to the pathological vascular remodelling process. Due to the reversible nature of post-translational protein acetylation, the therapeutic efficacy of numerous small-molecule inhibitors (vorinostat, valproic acid, sodium butyrate, mocetinostat, entinostat, tubastatin A, apabetalone, JQ1 and resveratrol) have been evaluated in different preclinical models of cardiovascular disease, which revealed the promising therapeutic benefits of targeting histone acetylation pathways in the attenuation of cardiac hypertrophy, fibrosis, left heart dysfunction, PH and RHF. This review also emphasizes the need for deeper molecular insights into the contribution of epigenetic changes to PH pathogenesis and therapeutic evaluation of isoform-specific modulation in ex vivo and in vivo models of PH and RHF. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
Topics: Acetylation; Cell Cycle Proteins; Histones; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Nuclear Proteins; Protein Processing, Post-Translational; Transcription Factors
PubMed: 31749139
DOI: 10.1111/bph.14932 -
Chemistry & Biodiversity Jul 2023Grapefruit peel polysaccharide has antioxidant, antitumor, hypoglycemic and other biological activities, and chemical modification can further improve the properties of...
Grapefruit peel polysaccharide has antioxidant, antitumor, hypoglycemic and other biological activities, and chemical modification can further improve the properties of the polysaccharide. Acetylation modification of polysaccharides has the advantages of simple operation, low cost and little pollution, and is widely used at present. Different degrees of acetylation modification have different effects on the properties of polysaccharides, so it is necessary to optimize the preparation technology of acetylated grapefruit peel polysaccharides. In this article, acetylated grapefruit peel polysaccharide was prepared by acetic anhydride method. With the degree of acetyl substitution as the evaluation index, combined with the analysis of sugar content and protein content in the polysaccharide before and after modification, the effects of three feeding ratios of 1:0.6, 1 : 1.2 and 1 : 1.8 (polysaccharide: acetic anhydride, mass/volume) on acetylation modification were explored through single factor experiments. The results showed that the optimum ratio of material to liquid for acetylation modification of grapefruit peel polysaccharide was 1:0.6. Under these conditions, the degree of substitution of acetylated grapefruit peel polysaccharide was 0.323, the sugar content was 59.50 % and the protein content was 1.038 %. The results provide some reference for the study of acetylated grapefruit peel polysaccharide.
Topics: Citrus paradisi; Acetic Anhydrides; Polysaccharides; Sugars; Acetylation
PubMed: 37211951
DOI: 10.1002/cbdv.202300167 -
Journal of Proteome Research Dec 2023Among the various cell types that constitute the liver, Kupffer cells (KCs) are responsible for the elimination of gut-derived foreign products. Protein lysine...
Among the various cell types that constitute the liver, Kupffer cells (KCs) are responsible for the elimination of gut-derived foreign products. Protein lysine acetylation (Kac) and lactylation (Kla) are dynamic and reversible post-translational modifications, and various global acylome studies have been conducted for liver and liver-derived cells. However, no such studies have been conducted on KCs. In this study, we identified 2198 Kac sites in 925 acetylated proteins and 289 Kla sites in 181 lactylated proteins in immortalized mouse KCs using global acylome technology. The subcellular distributions of proteins with Kac and Kla site modifications differed. Similarly, the specific sequence motifs surrounding acetylated or lactylated lysine residues also showed differences. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to better understand the differentially expressed proteins in the studies by Kac and Kla. In the newly identified Kla, we found K82 lactylation in the high-mobility group box-1 protein in the neutrophil extracellular trap formation category using KEGG enrichment analyses. Here, we report the first proteomic survey of Kac and Kla in KCs.
Topics: Animals; Mice; Lysine; Kupffer Cells; Acetylation; Proteomics; Proteome; Protein Processing, Post-Translational
PubMed: 37897433
DOI: 10.1021/acs.jproteome.3c00156 -
Methods (San Diego, Calif.) Dec 2020Bromodomains (BRDs) are evolutionarily conserved protein domains that specifically recognize acetylated lysine, a common epigenetic mark on histone tails. They are found... (Review)
Review
Bromodomains (BRDs) are evolutionarily conserved protein domains that specifically recognize acetylated lysine, a common epigenetic mark on histone tails. They are found in 61 human proteins, including enzymes, scaffolding platforms, and transcriptional co-activators. BRD-containing proteins play important roles in chromatin remodeling and the regulation of gene expression. Importantly, disruptions of BRD functions have been reported in various diseases. The premise of BRD-containing proteins as therapeutic targets has led to the development of multiple BRD inhibitors, many of which are currently being investigated in clinical trials. Thus, in the last decade significant efforts have been devoted to elucidating BRD biology. Here, we review the emerging tools that contributed to these efforts, from the structural definition of BRDs to their functional characterization. We further highlight the methods that have allowed the systematic screening of BRD targets and the identification of their endogenous interactors. Interactome mapping tools, such as affinity purification and proximity-based biotinylation, have contributed to the elucidation of BRD functions and their involvement in signaling pathways. We also discuss how recent progress in proteomics may further enhance our understanding of the biology of BRDs.
Topics: Acetylation; Biotinylation; Epigenesis, Genetic; Histones; Humans; Lysine; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Interaction Maps; Protein Processing, Post-Translational; Proteomics; Transcription Factors
PubMed: 31726225
DOI: 10.1016/j.ymeth.2019.11.003 -
The Journal of Biological Chemistry Jun 2023The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces...
The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-CoA (AcCoA), which fuels essential metabolic pathways and is also the acyl donor for protein lysine acetylation. Histones are abundant and highly acetylated proteins, accounting for 40% to 75% of cellular protein acetylation. Notably, histone acetylation is sensitive to AcCoA availability, and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to AcCoA, suggesting that deacetylation could be mobilized as an AcCoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we used acetate-dependent, ATP citrate lyase-deficient mouse embryonic fibroblasts (Acly MEFs), and designed a pulse-chase experimental system to trace deacetylation-derived acetate and its incorporation into AcCoA. We found that dynamic protein deacetylation in Acly MEFs contributed carbons to AcCoA and proximal downstream metabolites. However, deacetylation had no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplied less than 10% of cellular AcCoA. Together, our data reveal that although histone acetylation is dynamic and nutrient-sensitive, its potential for maintaining cellular AcCoA-dependent metabolic pathways is limited compared to cellular demand.
Topics: Animals; Mice; Acetates; Acetyl Coenzyme A; Acetylation; Carbon; Fibroblasts; Histones; Cells, Cultured
PubMed: 37142219
DOI: 10.1016/j.jbc.2023.104772 -
Nucleic Acids Research Oct 2023Acetylation is a global post-translational modification that regulates various cellular processes. Bacterial acetylomic studies have revealed extensive acetylation of...
Acetylation is a global post-translational modification that regulates various cellular processes. Bacterial acetylomic studies have revealed extensive acetylation of ribosomal proteins. However, the role of acetylation in regulating ribosome function remains poorly understood. In this study, we systematically profiled ribosomal protein acetylation and identified a total of 289 acetylated lysine residues in 52 ribosomal proteins (r-proteins) from Salmonella Typhimurium. The majority of acetylated lysine residues of r-proteins were found to be regulated by both acetyltransferase Pat and metabolic intermediate acetyl phosphate. Our results show that acetylation plays a critical role in the assembly of the mature 70S ribosome complex by modulating r-proteins binding to rRNA. Moreover, appropriate acetylation is important for the interactions between elongation factors and polysomes, as well as regulating ribosome translation efficiency and fidelity. Dysregulation of acetylation could alter bacterial sensitivity to ribosome-targeting antibiotics. Collectively, our data suggest that the acetylation homeostasis of ribosomes is crucial for their assembly and function. Furthermore, this mechanism may represent a universal response to environmental signals across different cell types.
Topics: Acetylation; Homeostasis; Lysine; Protein Processing, Post-Translational; Ribosomal Proteins; Ribosomes; Salmonella typhimurium
PubMed: 37742082
DOI: 10.1093/nar/gkad768 -
Chemical Communications (Cambridge,... Jun 2022Posttranslational modifications, typically small chemical tags attached on amino acids following protein biosynthesis, have a profound effect on protein structure and... (Review)
Review
Posttranslational modifications, typically small chemical tags attached on amino acids following protein biosynthesis, have a profound effect on protein structure and function. Numerous chemically and structurally diverse posttranslational modifications, including methylation, acetylation, hydroxylation, and ubiquitination, have been identified and characterised on lysine residues in proteins. In this feature article, we focus on chemical tools that rely on the site-specific incorporation of unnatural amino acids into peptides and proteins to probe posttranslational modifications of lysine. We highlight that simple amino acid mimics enable detailed mechanistic and functional assignment of enzymes that install and remove such modifications, and proteins that specifically recognise lysine posttranslational modifications.
Topics: Acetylation; Amino Acids; Lysine; Protein Processing, Post-Translational; Proteins; Ubiquitination
PubMed: 35678513
DOI: 10.1039/d2cc00708h -
Molecules (Basel, Switzerland) Jan 2023The aim of the present study was to increase the value of rice protein concentrate (RPC) by improving the functional properties of a preparation subjected to acetylation...
The aim of the present study was to increase the value of rice protein concentrate (RPC) by improving the functional properties of a preparation subjected to acetylation and analyze the impact of this chemical modification on chemical composition, digestibility, and protein patterning using SDS-PAGE electrophoresis and FT-IR spectroscopy. In the modified samples, the protein content increased (80.90-83.10 g/100 g cf. 74.20 g/100 g in the control). Electrophoresis revealed that the content of the main rice protein fractions (prolamin and glutelin) decreased as the concentration of the modifying reagent increased. Through spectroscopic analysis, wavenumbers, corresponding to the presence of proteins or lipids, aromatic systems, and carbohydrates, were observed. The use of acetic anhydride did not change the digestibility of the modified RPC significantly when compared to that of the control sample. The acetylation of the RPC caused a significant increase in its emulsifying properties at pH 8 (1.83-14.74%) and its water-binding capacity but did not have a statistically significant impact on the oil-absorption capacity. There was a slight increase in protein solubility and a decrease in foaming capacity in the modified RPC.
Topics: Acetylation; Oryza; Plant Proteins; Spectroscopy, Fourier Transform Infrared; Chemical Phenomena; Solubility
PubMed: 36677829
DOI: 10.3390/molecules28020770 -
Autophagy Dec 2021Aberrant chaperone-mediated autophagy (CMA) activation has been suggested as a tumorigenesis-promoting event in various cancers, although its roles in prostate cancer...
Aberrant chaperone-mediated autophagy (CMA) activation has been suggested as a tumorigenesis-promoting event in various cancers, although its roles in prostate cancer (PCa) remain elusive. Emerging evidence indicates that , a prostate-specific and androgen-responsive gene, contributes to the malignant progression of PCa. Here, we demonstrate that TPD52 enhances CMA activation by interacting with HSPA8/HSC70 and enhancing substrate degradation in PCa. Elevation of TPD52 is essential for CMA-induced PCa cell proliferation and stress resistance and . Furthermore, TPD52 is acetylated by KAT2B at K163, which is a process that can be antagonized by HDAC2. Inactivation of HDAC2 results in elevated TPD52 acetylation, which compromises the interaction between TPD52 and HSPA8, leading to impaired CMA function and tumor growth . Taken together, our findings reveal that acetylation-dependent regulation of TPD52 modulates CMA oncogenic function in PCa, thereby suggesting the possibility of targeting the TPD52-mediated CMA pathway to control the progression of PCa.: CMA: chaperone-mediated autophagy; HDAC2: histone deacetylase 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KAT2B: lysine acetyltransferase 2B; LAMP2A: lysosomal associated membrane protein 2A; PCa: prostate cancer; TPD52: tumor protein D52.
Topics: Acetylation; Autophagy; Chaperone-Mediated Autophagy; Humans; Lysosomal-Associated Membrane Protein 2; Lysosomes; Male; Neoplasm Proteins; Prostatic Neoplasms; Protein Isoforms
PubMed: 34034634
DOI: 10.1080/15548627.2021.1917130 -
Cell Communication and Signaling : CCS Feb 2024The phenomenon of phase separation is quite common in cells, and it is involved in multiple processes of life activities. However, the current research on the... (Review)
Review
The phenomenon of phase separation is quite common in cells, and it is involved in multiple processes of life activities. However, the current research on the correlation between protein modifications and phase separation and the interference with the tendency of phase separation has some limitations. Here we focus on several post-translational modifications of proteins, including protein phosphorylation modification at multiple sites, methylation modification, acetylation modification, ubiquitination modification, SUMOylation modification, etc., which regulate the formation of phase separation and the stability of phase separation structure through multivalent interactions. This regulatory role is closely related to the development of neurodegenerative diseases, tumors, viral infections, and other diseases, and also plays essential functions in environmental stress, DNA damage repair, transcriptional regulation, signal transduction, and cell homeostasis of living organisms, which provides an idea to explore the interaction between novel protein post-translational modifications and phase separation. Video Abstract.
Topics: Phase Separation; Protein Processing, Post-Translational; Ubiquitination; Phosphorylation; Proteins; Acetylation
PubMed: 38347544
DOI: 10.1186/s12964-023-01380-1