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Biotechnology Advances Dec 2021Protein acetylation is an evolutionarily conserved posttranslational modification. It affects enzyme activity, metabolic flux distribution, and other critical... (Review)
Review
Protein acetylation is an evolutionarily conserved posttranslational modification. It affects enzyme activity, metabolic flux distribution, and other critical physiological and biochemical processes by altering protein size and charge. Protein acetylation may thus be a promising tool for metabolic regulation to improve target production and conversion efficiency in fermentation. Here we review the role of protein acetylation in bacterial physiology and metabolism and describe applications of protein acetylation in fermentation engineering and strategies for regulating acetylation status. Although protein acetylation has become a hot topic, the regulatory mechanisms have not been fully characterized. We propose future research directions in protein acetylation.
Topics: Acetylation; Bacteria; Bacterial Proteins; Lysine; Protein Processing, Post-Translational
PubMed: 34624455
DOI: 10.1016/j.biotechadv.2021.107842 -
Biochimica Et Biophysica Acta. Gene... Feb 2021Histone post-translational modifications are essential for the regulation of gene expression in eukaryotes. Gcn5 (KAT2A) is a histone acetyltransferase that catalyzes... (Review)
Review
Histone post-translational modifications are essential for the regulation of gene expression in eukaryotes. Gcn5 (KAT2A) is a histone acetyltransferase that catalyzes the post-translational modification at multiple positions of histone H3 through the transfer of acetyl groups to the free amino group of lysine residues. Gcn5 catalyzes histone acetylation in the context of a HAT module containing the Ada2, Ada3 and Sgf29 subunits of the parent megadalton SAGA transcriptional coactivator complex. Biochemical and structural studies have elucidated mechanisms for Gcn5's acetyl- and other acyltransferase activities on histone substrates, for histone H3 phosphorylation and histone H3 methylation crosstalks with histone H3 acetylation, and for how Ada2 increases Gcn5's histone acetyltransferase activity. Other studies have identified Ada2 isoforms in SAGA-related complexes and characterized variant Gcn5 HAT modules containing these Ada2 isoforms. In this review, we highlight biochemical and structural studies of Gcn5 and its functional interactions with Ada2, Ada3 and Sgf29.
Topics: Acetylation; Cryoelectron Microscopy; Histone Acetyltransferases; Histones; Isoenzymes; Methylation; Multienzyme Complexes; Phosphorylation; Protein Processing, Post-Translational; Saccharomyces cerevisiae Proteins; Transcription Factors; p300-CBP Transcription Factors
PubMed: 32890768
DOI: 10.1016/j.bbagrm.2020.194629 -
Cell Reports Feb 2024Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during...
Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.
Topics: Histones; Acetylation; Gene Expression; Lactic Acid; Macrophages
PubMed: 38329873
DOI: 10.1016/j.celrep.2024.113746 -
International Journal of Molecular... Sep 2022During viral infection, both host and viral proteins undergo post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and... (Review)
Review
During viral infection, both host and viral proteins undergo post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, and acetylation, which play critical roles in viral replication, pathogenesis, and host antiviral responses. Protein acetylation is one of the most important PTMs and is catalyzed by a series of acetyltransferases that divert acetyl groups from acetylated molecules to specific amino acid residues of substrates, affecting chromatin structure, transcription, and signal transduction, thereby participating in the cell cycle as well as in metabolic and other cellular processes. Acetylation of host and viral proteins has emerging roles in the processes of virus adsorption, invasion, synthesis, assembly, and release as well as in host antiviral responses. Methods to study protein acetylation have been gradually optimized in recent decades, providing new opportunities to investigate acetylation during viral infection. This review summarizes the classification of protein acetylation and the standard methods used to map this modification, with an emphasis on viral and host protein acetylation during viral infection.
Topics: Acetylation; Acetyltransferases; Amino Acids; Antiviral Agents; Chromatin; Humans; Protein Processing, Post-Translational; Viral Proteins; Virus Diseases
PubMed: 36232610
DOI: 10.3390/ijms231911308 -
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 -
Nature Communications Dec 2022Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of...
Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of the acetyl lysine reader BRD4 that binds to the acetylase p300 and enables formation of long-range intra- and interchromosomal interactions. We here examine how acetylation reading and writing enable formation of such interactions. We show that NUT contains an acidic transcriptional activation domain that binds to the TAZ2 domain of p300. We use NMR to investigate the structure of the complex and found that the TAZ2 domain has an autoinhibitory role for p300. NUT-TAZ2 interaction or mutations found in cancer that interfere with autoinhibition by TAZ2 allosterically activate p300. p300 activation results in a self-organizing, acetylation-dependent feed-forward reaction that enables long-range interactions by bromodomain multivalent acetyl-lysine binding. We discuss the implications for chromatin organisation, gene regulation and dysregulation in disease.
Topics: Acetylation; Nuclear Proteins; Lysine; Transcription Factors; Chromatin
PubMed: 36522330
DOI: 10.1038/s41467-022-35375-2 -
International Journal of Molecular... Nov 2020The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein... (Review)
Review
The protein acetylation of either the α-amino groups of amino-terminal residues or of internal lysine or cysteine residues is one of the major posttranslational protein modifications that occur in the cell with repercussions at the protein as well as at the metabolome level. The lysine acetylation status is determined by the opposing activities of lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), which add and remove acetyl groups from proteins, respectively. A special group of KDACs, named sirtuins, that require NAD as a substrate have received particular attention in recent years. They play critical roles in metabolism, and their abnormal activity has been implicated in several diseases. Conversely, the modulation of their activity has been associated with protection from age-related cardiovascular and metabolic diseases and with increased longevity. The benefits of either activating or inhibiting these enzymes have turned sirtuins into attractive therapeutic targets, and considerable effort has been directed toward developing specific sirtuin modulators. This review summarizes the protein acylation/deacylation processes with a special focus on the current developments in the sirtuin research field.
Topics: Acetylation; Aging; Cardiovascular Diseases; Humans; Metabolic Diseases; Protein Processing, Post-Translational; Sirtuins
PubMed: 33203121
DOI: 10.3390/ijms21228609 -
Methods in Molecular Biology (Clifton,... 2021Posttranslational modifications of NF-κB, including phosphorylation, acetylation, and methylation, have emerged as important regulatory mechanisms to control the...
Posttranslational modifications of NF-κB, including phosphorylation, acetylation, and methylation, have emerged as important regulatory mechanisms to control the transcriptional outcomes of this important transcription factor. These modifications work independently, sequentially or in combination to modulate the diverse biological functions of NF-κB in cancer and inflammatory response. Here, we describe some experimental methods to detect the in vitro and in vivo phosphorylation and acetylation of NF-κB, specifically focusing on the RelA subunit of NF-κB. These methods include labeling the phospho- or acetyl- groups with radioisotopes in vitro and immunoblotting with site-specific anti-phospho-serine or acetyl-lysine antibodies in culture cells and tissue samples.
Topics: Acetylation; Gene Expression Regulation; NF-kappa B; Phosphorylation; Protein Processing, Post-Translational; Transcription Factor RelA
PubMed: 34236629
DOI: 10.1007/978-1-0716-1669-7_1 -
Journal of Cellular Biochemistry Apr 2022Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues... (Review)
Review
Acetylation of proteins seems a widespread process found in the three domains of life. Several studies have shown that besides histones, acetylation of lysine residues also occurs in non-nuclear proteins. Hence, it has been suggested that this covalent modification is a mechanism that might regulate diverse metabolic pathways by modulating enzyme activity, stability, and/or subcellular localization or interaction with other proteins. However, protein acetylation levels seem to have low correlation with modification of enzyme activity and pathway fluxes. In addition, the results obtained with mutant enzymes that presumably mimic acetylation have frequently been over-interpreted. Moreover, there is a generalized lack of rigorous enzyme kinetic analysis in parallel to acetylation level determinations. The purpose of this review is to analyze the current findings on the impact of acetylation on metabolic enzymes and its repercussion on metabolic pathways function/regulation.
Topics: Acetylation; Histones; Kinetics; Metabolic Networks and Pathways; Protein Processing, Post-Translational
PubMed: 34931340
DOI: 10.1002/jcb.30197 -
Expert Review of Proteomics Nov 2021Lysine acetylation is a reversible post-translational modification (PTM) regulated through the action of specific types of enzymes: lysine acetyltransferases (KATs) and... (Review)
Review
INTRODUCTION
Lysine acetylation is a reversible post-translational modification (PTM) regulated through the action of specific types of enzymes: lysine acetyltransferases (KATs) and lysine deacetylases (HDACs), in addition to bromodomains, which are a group of conserved domains which identify acetylated lysine residues, several of the players in the process of protein acetylation, including enzymes and bromodomain-containing proteins, have been related to the progression of several diseases. The combination of high-resolution mass spectrometry-based proteomics, and immunoprecipitation to enrich acetylated peptides has contributed in recent years to expand the knowledge about this PTM described initially in histones and nuclear proteins, and is currently reported in more than 5000 human proteins, that are regulated by this PTM.
AREAS COVERED
This review presents an overview of the main participant elements, the scenario in the development of protein lysine acetylation, and its role in different human pathologies.
EXPERT OPINION
Acetylation targets are practically all cellular processes in eukaryotes and prokaryotes organisms. Consequently, this modification has been linked to many pathologies like cancer, viral infection, obesity, diabetes, cardiovascular, and nervous system-associated diseases, to mention a few relevant examples. Accordingly, some intermediate mediators in the acetylation process have been projected as therapeutic targets.
Topics: Acetylation; Histones; Humans; Lysine; Protein Processing, Post-Translational; Proteomics
PubMed: 34791964
DOI: 10.1080/14789450.2021.2007766