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Clinical Epigenetics Jul 2019Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation.... (Review)
Review
Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation. Endogenous short peptides, resulting from proteolytic cleavage of proteins or upon translation of non-annotated out of frame transcripts, can block DNA methylation and hereby regulate gene expression. Peptides entering the body by digestion of food-related proteins can modulate DNA methylation and/or histone acetylation while environmental peptides, synthesized by bacteria, fungi, and marine sponges, mainly inhibit histone deacetylation. In addition, synthetic peptides that reverse or inhibit different epigenetic modifications of both histones and the DNA can be developed as well. Next to these DNA and histone modifications, peptides can also influence the expression of non-coding RNAs such as lncRNAs and the maturation of miRNAs.Seen the advantages over small molecules, the development of peptide therapeutics is an interesting approach to treat diseases with a strong epigenetic basis like cancer and Alzheimer's disease. To date, only a limited number of drugs with a proven epigenetic mechanism of action have been approved by the FDA of which two (romidepsin and nesiritide) are peptides. A large knowledge gap concerning epigenetic effects of peptides is present, and this class of molecules deserves more attention in the development as epigenetic modulators. In addition, none of the currently approved peptide drugs are under investigation for their potential effects on epigenetics, hampering drug repositioning of these peptides to other indications with an epigenetic etiology.
Topics: Acetylation; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Peptides
PubMed: 31300053
DOI: 10.1186/s13148-019-0700-7 -
Plant Communications Jan 2022Lysine acetylation (LysAc) is a conserved and important post-translational modification (PTM) that plays a key role in plant physiological and metabolic processes. Based... (Review)
Review
Lysine acetylation (LysAc) is a conserved and important post-translational modification (PTM) that plays a key role in plant physiological and metabolic processes. Based on advances in Lys-acetylated protein immunoenrichment and mass-spectrometric technology, LysAc proteomics studies have been performed in many species. Such studies have made substantial contributions to our understanding of plant LysAc, revealing that Lys-acetylated histones and nonhistones are involved in a broad spectrum of plant cellular processes. Here, we present an extensive overview of recent research on plant Lys-acetylproteomes. We provide in-depth insights into the characteristics of plant LysAc modifications and the mechanisms by which LysAc participates in cellular processes and regulates metabolism and physiology during plant growth and development. First, we summarize the characteristics of LysAc, including the properties of Lys-acetylated sites, the motifs that flank Lys-acetylated lysines, and the dynamic alterations in LysAc among different tissues and developmental stages. We also outline a map of Lys-acetylated proteins in the Calvin-Benson cycle and central carbon metabolism-related pathways. We then introduce some examples of the regulation of plant growth, development, and biotic and abiotic stress responses by LysAc. We discuss the interaction between LysAc and N-terminal acetylation and the crosstalk between LysAc and other PTMs, including phosphorylation and succinylation. Finally, we propose recommendations for future studies in the field. We conclude that LysAc of proteins plays an important role in the regulation of the plant life cycle.
Topics: Acetylation; Lysine; Plant Proteins; Protein Processing, Post-Translational; Proteome
PubMed: 35059632
DOI: 10.1016/j.xplc.2021.100266 -
Molecular Microbiology May 2023Lysine acetylation is one of the most abundant post-translational modifications in nature, affecting many key biological pathways in both prokaryotes and eukaryotes. It... (Review)
Review
Lysine acetylation is one of the most abundant post-translational modifications in nature, affecting many key biological pathways in both prokaryotes and eukaryotes. It has not been long since technological advances led to understanding of the roles of acetylation in biological processes. Most of those studies were based on proteomic analyses, which have identified thousands of acetylation sites in a wide range of proteins. However, the specific role of individual acetylation event remains largely unclear, mostly due to the existence of multiple acetylation and dynamic changes of acetylation levels. To solve these problems, the genetic code expansion technique has been applied in protein acetylation studies, facilitating the incorporation of acetyllysine into a specific lysine position to generate a site-specifically acetylated protein. By this method, the effects of acetylation at a specific lysine residue can be characterized with minimal interferences. Here, we summarized the development of the genetic code expansion technique for lysine acetylation and recent studies on lysine acetylation of citrate acid cycle enzymes in bacteria by this approach, providing a practical application of the genetic code expansion technique in protein acetylation studies.
Topics: Lysine; Citric Acid Cycle; Acetylation; Proteomics; Proteins; Protein Processing, Post-Translational; Genetic Code
PubMed: 36890576
DOI: 10.1111/mmi.15052 -
Autophagy 2018PIK3C3/VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3) converts phosphatidylinositol (PtdIns) to phosphatidylinositol-3-phosphate (PtdIns3P), sustaining...
PIK3C3/VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3) converts phosphatidylinositol (PtdIns) to phosphatidylinositol-3-phosphate (PtdIns3P), sustaining macroautophagy/autophagy and endosomal transport. So far, facilitating the assembly of the PIK3C3/VPS34-BECN1-PIK3R4/VPS15/p150 core complex at distinct membranes is the only known way to activate PIK3C3/VPS34 in cells. We have recently revealed a novel mechanism that regulates PIK3C3/VPS34 activation; cellular PIK3C3/VPS34 is repressed under nutrient-rich conditions by EP300/p300-mediated acetylation. Following nutrient-deprivation that drops EP300 activity, PIK3C3/VPS34 is liberated by deacetylation. Intriguingly, while deacetylation of the N-terminal K29 residue accounts for core complex formation, deacetylation at the C-terminal K771 site determines the binding of PIK3C3/VPS34 to its substrate PtdIns. In vitro and in cell evidence shows that EP300-dependent acetylation and deacetylation is a switch for turning off/on PIK3C3/VPS34 in which deacetylation of K771 is required for its full activation. This PIK3C3/VPS34 activation mechanism is utilized not only by starvation-induced autophagy but also by autophagy without the involvement of AMPK, MTORC1 or ULK1. These findings suggest an alternative circuit in cells for PIK3C3/VPS34 activation, which is involved in membrane transformations in response to metabolic and nonmetabolic cues.
Topics: Acetylation; Autophagy; Autophagy-Related Protein-1 Homolog; Autophagy-Related Proteins; Class III Phosphatidylinositol 3-Kinases
PubMed: 28980854
DOI: 10.1080/15548627.2017.1385676 -
Advances in Experimental Medicine and... 2019Mitochondria have a central role in cellular metabolism and reversible post-translational modifications regulate activity of mitochondrial proteins. Thanks to advances...
Mitochondria have a central role in cellular metabolism and reversible post-translational modifications regulate activity of mitochondrial proteins. Thanks to advances in proteomics, lysine acetylation has arisen as an important post-translational modification in the mitochondrion. During acetylation an acetyl group is covalently attached to the epsilon amino group in the side chain of lysine residues using acetyl-CoA as the substrate donor. Therefore the positive charge is neutralized, and this can affect the function of proteins thereby regulating enzyme activity, protein interactions, and protein stability. The major deacetylase in mitochondria is SIRT3 whose activity regulates many mitochondrial enzymes. The method of choice for the analysis of acetylated proteins foresees the combination of mass spectrometry-based proteomics with affinity enrichment techniques. Beyond the identification of lysine-acetylated proteins, many studies are moving towards the characterization of acetylated patterns in different diseases. Indeed, modifications in lysine acetylation status can directly alter mitochondrial function and, therefore, be linked to human diseases such as metabolic diseases, cancer, myocardial injury and neurodegenerative diseases. Despite the progress in the characterization of different lysine acetylation sites, additional studies are needed to differentiate the specific changes with a significant biological relevance.
Topics: Acetylation; Humans; Lysine; Mitochondria; Mitochondrial Proteins; Phenotype; Protein Processing, Post-Translational
PubMed: 31452135
DOI: 10.1007/978-981-13-8367-0_4 -
PloS One 2017Neisseria gonorrhoeae, the causative agent of gonorrhea, has a number of factors known to contribute to pathogenesis; however, a full understanding of these processes...
Neisseria gonorrhoeae, the causative agent of gonorrhea, has a number of factors known to contribute to pathogenesis; however, a full understanding of these processes and their regulation has proven to be elusive. Post-translational modifications (PTMs) of bacterial proteins are now recognized as one mechanism of protein regulation. In the present study, Western blot analyses, with an anti-acetyl-lysine antibody, indicated that a large number of gonococcal proteins are post-translationally modified. Previous work has shown that Nε-lysine acetylation can occur non-enzymatically with acetyl-phosphate (AcP) as the acetyl donor. In the current study, an acetate kinase mutant (1291ackA), which accumulates AcP, was generated in N. gonorrhoeae. Broth cultures of N. gonorrhoeae 1291wt and 1291ackA were grown, proteins extracted and digested, and peptides containing acetylated-lysines (K-acetyl) were affinity-enriched from both strains. Mass spectrometric analyses of these samples identified a total of 2686 unique acetylation sites. Label-free relative quantitation of the K-acetyl peptides derived from the ackA and wild-type (wt) strains demonstrated that 109 acetylation sites had an ackA/wt ratio>2 and p-values <0.05 in at least 2/3 of the biological replicates and were designated as "AckA-dependent". Regulated K-acetyl sites were found in ribosomal proteins, central metabolism proteins, iron acquisition and regulation proteins, pilus assembly and regulation proteins, and a two-component response regulator. Since AckA is part of a metabolic pathway, comparative growth studies of the ackA mutant and wt strains were performed. The mutant showed a growth defect under aerobic conditions, an inability to grow anaerobically, and a defect in biofilm maturation. In conclusion, the current study identified AckA-dependent acetylation sites in N. gonorrhoeae and determined that these sites are found in a diverse group of proteins. This work lays the foundation for future studies focusing on specific acetylation sites that may have relevance in gonococcal pathogenesis and metabolism.
Topics: Acetate Kinase; Acetylation; Bacterial Proteins; Gene Expression Regulation, Bacterial; Mass Spectrometry; Metabolic Networks and Pathways; Neisseria gonorrhoeae; Phosphorylation; Protein Processing, Post-Translational
PubMed: 28654654
DOI: 10.1371/journal.pone.0179621 -
Nature Communications Nov 2018Emerging evidence highlights protein acetylation, a prevalent lysine posttranslational modification, as a regulatory mechanism and promising therapeutic target in human...
Emerging evidence highlights protein acetylation, a prevalent lysine posttranslational modification, as a regulatory mechanism and promising therapeutic target in human viral infections. However, how infections dynamically alter global cellular acetylation or whether viral proteins are acetylated remains virtually unexplored. Here, we establish acetylation as a highly-regulated molecular toggle of protein function integral to the herpesvirus human cytomegalovirus (HCMV) replication. We offer temporal resolution of cellular and viral acetylations. By interrogating dynamic protein acetylation with both protein abundance and subcellular localization, we discover finely tuned spatial acetylations across infection time. We determine that lamin acetylation at the nuclear periphery protects against virus production by inhibiting capsid nuclear egress. Further studies within infectious viral particles identify numerous acetylations, including on the viral transcriptional activator pUL26, which we show represses virus production. Altogether, this study provides specific insights into functions of cellular and viral protein acetylations and a valuable resource of dynamic acetylation events.
Topics: Acetylation; Cell Nucleus; Cytomegalovirus; Cytomegalovirus Infections; Host-Pathogen Interactions; Humans; Lamins; Proteins; Viral Proteins; Virus Replication
PubMed: 30470744
DOI: 10.1038/s41467-018-07179-w -
Journal of Proteome Research Jan 2021Acetylation was initially discovered as a post-translational modification (PTM) on the unstructured, highly basic N-terminal tails of eukaryotic histones in the 1960s.... (Review)
Review
Acetylation was initially discovered as a post-translational modification (PTM) on the unstructured, highly basic N-terminal tails of eukaryotic histones in the 1960s. Histone acetylation constitutes part of the "histone code", which regulates chromosome compaction and various DNA processes such as gene expression, recombination, and DNA replication. In bacteria, nucleoid-associated proteins (NAPs) are responsible these functions in that they organize and compact the chromosome and regulate some DNA processes. The highly conserved DNABII family of proteins are considered functional homologues of eukaryotic histones despite having no sequence or structural conservation. Within the past decade, a growing interest in N-lysine acetylation led to the discovery that hundreds of bacterial proteins are acetylated with diverse cellular functions, in direct contrast to the original thought that this was a rare phenomenon. Similarly, other previously undiscovered bacterial PTMs, like serine, threonine, and tyrosine phosphorylation, have also been characterized. In this review, the various PTMs that were discovered among DNABII family proteins, specifically histone-like protein (HU) orthologues, from large-scale proteomic studies are discussed. The functional significance of these modifications and the enzymes involved are also addressed. The discovery of novel PTMs on these proteins begs this question: is there a histone-like code in bacteria?
Topics: Acetylation; Bacteria; Histone Code; Histones; Protein Processing, Post-Translational; Proteomics
PubMed: 32962352
DOI: 10.1021/acs.jproteome.0c00442 -
Trends in Biochemical Sciences Feb 2011Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic... (Review)
Review
Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic analyses on protein acetylation uncovered a large number of acetylated proteins in the cytoplasm and mitochondria, including most enzymes involved in intermediate metabolism. Acetylation regulates metabolic enzymes by multiple mechanisms, including via enzymatic activation or inhibition, and by influencing protein stability. Conversely, non-nuclear NAD(+)-dependent sirtuin deacetylases can regulate cellular and organismal metabolism, possibly through direct deacetylation of metabolic enzymes. Furthermore, acetylation of metabolic enzymes is highly conserved from prokaryotes to eukaryotes. Given the frequent occurrence of metabolic dysregulation in diabetes, obesity and cancer, enzymes modulating acetylation could provide attractive targets for therapeutic intervention for these diseases.
Topics: Acetylation; Animals; Humans; Metabolic Networks and Pathways; Protein Processing, Post-Translational; Proteins; Sirtuins
PubMed: 20934340
DOI: 10.1016/j.tibs.2010.09.003 -
Expert Review of Anticancer Therapy Jun 2010Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of... (Review)
Review
Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein-protein and protein-DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed.
Topics: Acetylation; Chromosomal Proteins, Non-Histone; Histone Deacetylase Inhibitors; Humans; Neoplasms
PubMed: 20553216
DOI: 10.1586/era.10.62