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Frontiers in Endocrinology 2022Polycystic ovary syndrome (PCOS) is a lifelong reproductive, metabolic, and psychiatric disorder that affects 5-18% of women, which is associated with a significantly... (Review)
Review
Polycystic ovary syndrome (PCOS) is a lifelong reproductive, metabolic, and psychiatric disorder that affects 5-18% of women, which is associated with a significantly increased lifetime risk of concomitant diseases, including type 2 diabetes, psychiatric disorders, and gynecological cancers. Posttranslational modifications (PTMs) play an important role in changes in protein function and are necessary to maintain cellular viability and biological processes, thus their maladjustment can lead to disease. Growing evidence suggests the association between PCOS and posttranslational modifications. This article mainly reviews the research status of phosphorylation, methylation, acetylation, and ubiquitination, as well as their roles and molecular mechanisms in the development of PCOS. In addition, we briefly summarize research and clinical trials of PCOS therapy to advance our understanding of agents that can be used to target phosphorylated, methylated, acetylated, and ubiquitinated PTM types. It provides not only ideas for future research on the mechanism of PCOS but also ideas for PCOS treatments with therapeutic potential.
Topics: Female; Humans; Polycystic Ovary Syndrome; Diabetes Mellitus, Type 2; Protein Processing, Post-Translational; Acetylation; Proteins
PubMed: 36277727
DOI: 10.3389/fendo.2022.1024320 -
Eukaryotic Cell Dec 2014Cells sense and appropriately respond to the physical conditions and availability of nutrients in their environment. This sensing of the environment and consequent... (Review)
Review
Cells sense and appropriately respond to the physical conditions and availability of nutrients in their environment. This sensing of the environment and consequent cellular responses are orchestrated by a multitude of signaling pathways and typically involve changes in transcription and metabolism. Recent discoveries suggest that the signaling and transcription machineries are regulated by signals which are derived from metabolism and reflect the metabolic state of the cell. Acetyl coenzyme A (CoA) is a key metabolite that links metabolism with signaling, chromatin structure, and transcription. Acetyl-CoA is produced by glycolysis as well as other catabolic pathways and used as a substrate for the citric acid cycle and as a precursor in synthesis of fatty acids and steroids and in other anabolic pathways. This central position in metabolism endows acetyl-CoA with an important regulatory role. Acetyl-CoA serves as a substrate for lysine acetyltransferases (KATs), which catalyze the transfer of acetyl groups to the epsilon-amino groups of lysines in histones and many other proteins. Fluctuations in the concentration of acetyl-CoA, reflecting the metabolic state of the cell, are translated into dynamic protein acetylations that regulate a variety of cell functions, including transcription, replication, DNA repair, cell cycle progression, and aging. This review highlights the synthesis and homeostasis of acetyl-CoA and the regulation of transcriptional and signaling machineries in yeast by acetylation.
Topics: Acetyl Coenzyme A; Acetylation; Animals; Homeostasis; Humans; Protein Processing, Post-Translational; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 25326522
DOI: 10.1128/EC.00189-14 -
International Journal of Molecular... Nov 2020Elp3, the catalytic subunit of the eukaryotic Elongator complex, is a lysine acetyltransferase that acetylates the C5 position of wobble-base uridines (U) in transfer... (Review)
Review
Elp3, the catalytic subunit of the eukaryotic Elongator complex, is a lysine acetyltransferase that acetylates the C5 position of wobble-base uridines (U) in transfer RNAs (tRNAs). This Elongator-dependent RNA acetylation of anticodon bases affects the ribosomal translation elongation rates and directly links acetyl-CoA metabolism to both protein synthesis rates and the proteome integrity. Of note, several human diseases, including various cancers and neurodegenerative disorders, correlate with the dysregulation of Elongator's tRNA modification activity. In this review, we focus on recent findings regarding the structure of Elp3 and the role of acetyl-CoA during its unique modification reaction.
Topics: Acetylation; Animals; Base Sequence; Binding Sites; Histone Acetyltransferases; Humans; Lysine; Nerve Tissue Proteins; Peptide Chain Elongation, Translational; RNA Processing, Post-Transcriptional; RNA, Transfer; Uridine
PubMed: 33152999
DOI: 10.3390/ijms21218209 -
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 -
Nature Structural & Molecular Biology Oct 2019The bromodomain (BrD) is a conserved structural module found in chromatin- and transcription-associated proteins that acts as the primary reader for acetylated lysine... (Review)
Review
The bromodomain (BrD) is a conserved structural module found in chromatin- and transcription-associated proteins that acts as the primary reader for acetylated lysine residues. This basic activity endows BrD proteins with versatile functions in the regulation of protein-protein interactions mediating chromatin-templated gene transcription, DNA recombination, replication and repair. Consequently, BrD proteins are involved in the pathogenesis of numerous human diseases. In this Review, we highlight our current understanding of BrD biology, and discuss the latest development of small-molecule inhibitors targeting BrDs as emerging epigenetic therapies for cancer and inflammatory disorders.
Topics: Acetylation; Animals; Drug Discovery; Epigenesis, Genetic; Histone Code; Histones; Humans; Inflammation; Models, Molecular; Neoplasms; Protein Domains; Small Molecule Libraries; Transcription Factors
PubMed: 31582847
DOI: 10.1038/s41594-019-0309-8 -
Essays in Biochemistry 2012Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria... (Review)
Review
Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria are acetylated, of which the majority are involved in some aspect of energy metabolism. Mitochondrial protein acetylation is regulated by SIRT3 (sirtuin 3), a member of the sirtuin family of NAD+-dependent protein deacetylases that has recently been identified as a key modulator of energy homoeostasis. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and contribute to mitochondrial dysfunction. This chapter presents a review of the functional impact of mitochondrial protein acetylation, and its regulation by SIRT3.
Topics: Acetylation; Animals; Humans; Mitochondria; Mitochondrial Proteins; Models, Biological; Sirtuin 3
PubMed: 22708561
DOI: 10.1042/bse0520023 -
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 -
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 -
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