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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 -
Journal of the American Chemical Society Mar 2023The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and...
The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins are a family of NAD-dependent HDAC enzymes, and one member, sirtuin 6 (Sirt6), influences DNA repair, transcription, and aging. Here, we demonstrate that Sirt6 is efficient at deacetylating several histone H3 acetylation sites, including its canonical site Lys9, in the context of nucleosomes but not free acetylated histone H3 protein substrates. By installing a chemical warhead at the Lys9 position of histone H3, we trap a catalytically poised Sirt6 in complex with a nucleosome and employ this in cryo-EM structural analysis. The structure of Sirt6 bound to a nucleosome reveals extensive interactions between distinct segments of Sirt6 and the H2A/H2B acidic patch and nucleosomal DNA, which accounts for the rapid deacetylation of nucleosomal H3 sites and the disfavoring of histone H2B acetylation sites. These findings provide a new framework for understanding how HDACs target and regulate chromatin.
Topics: Nucleosomes; Histones; Chromatin; Sirtuins; Acetylation; Glycosyltransferases; Catalysis
PubMed: 36930461
DOI: 10.1021/jacs.2c13512 -
Scientific Reports Sep 2023Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification...
Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5), also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis. Collectively, these findings not only identify regulatory pathways for HSPA5 acetylation during ferroptosis, but also highlight promising strategies to increase ferroptosis sensitivity in PDAC cells.
Topics: Humans; Acetylation; Carcinoma, Pancreatic Ductal; E1A-Associated p300 Protein; Endoplasmic Reticulum Chaperone BiP; Ferroptosis; Pancreatic Neoplasms
PubMed: 37696842
DOI: 10.1038/s41598-023-42136-8 -
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 -
Cell Proliferation Dec 2022SETDB1 is a methyltransferase responsible for the methylation of histone H3-lysine-9, which is mainly related to heterochromatin formation. SETDB1 is overexpressed in...
OBJECTIVES
SETDB1 is a methyltransferase responsible for the methylation of histone H3-lysine-9, which is mainly related to heterochromatin formation. SETDB1 is overexpressed in various cancer types and is associated with an aggressive phenotype. In agreement with its activity, it mainly exhibits a nuclear localization; however, in several cell types a cytoplasmic localization was reported. Here we looked for cytoplasmic functions of SETDB1.
METHODS
SETDB1 association with microtubules was detected by immunofluorescence and co-sedimentation. Microtubule dynamics were analysed during recovery from nocodazole treatment and by tracking microtubule plus-ends in live cells. Live cell imaging was used to study mitotic kinetics and protein-protein interaction was identified by co-immunoprecipitation.
RESULTS
SETDB1 co-sedimented with microtubules and partially colocalized with microtubules. SETDB1 partial silencing led to faster polymerization and reduced rate of catastrophe events of microtubules in parallel to reduced proliferation rate and slower mitotic kinetics. Interestingly, over-expression of either wild-type or catalytic dead SETDB1 altered microtubule polymerization rate to the same extent, suggesting that SETDB1 may affect microtubule dynamics by a methylation-independent mechanism. Moreover, SETDB1 co-immunoprecipitated with HDAC6 and tubulin acetylation levels were increased upon silencing of SETDB1.
CONCLUSIONS
Taken together, our study suggests a model in which SETDB1 affects microtubule dynamics by interacting with both microtubules and HDAC6 to enhance tubulin deacetylation. Overall, our results suggest a novel cytoplasmic role for SETDB1 in the regulation of microtubule dynamics.
Topics: Tubulin; Microtubules; Acetylation; Methylation
PubMed: 36330589
DOI: 10.1111/cpr.13348 -
Cells Nov 2022The tumor suppressor p53 is a transcription factor that regulates the expression of dozens of target genes and diverse physiological processes. To precisely regulate the... (Review)
Review
The tumor suppressor p53 is a transcription factor that regulates the expression of dozens of target genes and diverse physiological processes. To precisely regulate the p53 network, p53 undergoes various post-translational modifications and alters the selectivity of target genes. Acetylation plays an essential role in cell fate determination through the activation of p53. Although the acetylation of p53 has been examined, the underlying regulatory mechanisms remain unclear and, thus, have attracted the interest of researchers. We herein discuss the role of acetylation in the p53 pathway, with a focus on p53 acetyltransferases and deacetylases. We also review recent findings on the regulators of these enzymes to understand the mode of p53 acetylation from a broader perspective.
Topics: Tumor Suppressor Protein p53; Acetylation; Protein Processing, Post-Translational; Acetyltransferases; Transcription Factors
PubMed: 36497084
DOI: 10.3390/cells11233825 -
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 -
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 -
Cells Mar 2020-acetylation of sialic acid residues is one of the main modifications of gangliosides, and modulates ganglioside functions. -acetylation of gangliosides is dependent on... (Review)
Review
-acetylation of sialic acid residues is one of the main modifications of gangliosides, and modulates ganglioside functions. -acetylation of gangliosides is dependent on sialyl--acetyltransferases and sialyl--acetyl-esterase activities. CAS1 Domain-Containing Protein 1 (CASD1) is the only human sialyl--acetyltransferases (SOAT) described until now. -acetylated ganglioside species are mainly expressed during embryonic development and in the central nervous system in healthy adults, but are re-expressed during cancer development and are considered as markers of cancers of neuroectodermal origin. However, the specific biological roles of -acetylated gangliosides in developing and malignant tissues have not been extensively studied, mostly because of the requirement of specific approaches and tools for sample preparation and analysis. In this review, we summarize our current knowledge of ganglioside biosynthesis and expression in normal and pathological conditions, of ganglioside -acetylation analysis and expression in cancers, and of the possible use of -acetylated gangliosides as targets for cancer immunotherapy.
Topics: Acetylation; Animals; Gangliosides; Humans; Immunotherapy; Molecular Targeted Therapy; N-Acetylneuraminic Acid; Neoplasms
PubMed: 32192217
DOI: 10.3390/cells9030741 -
Seminars in Cancer Biology Oct 2022Acetylation represents one of the major post-translational protein modifications, which introduces an acetyl functional group into amino acids such as the lysine residue... (Review)
Review
Acetylation represents one of the major post-translational protein modifications, which introduces an acetyl functional group into amino acids such as the lysine residue to yield an acetate ester bond, neutralizing its positive charge. Regulation of protein functions by acetylation occurs in multiple ways, such as affecting protein stability, activity, localization, and interaction with other proteins or DNA. It has been well documented that the recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery can modulate histone acetylation status, which is directly involved in the dynamic regulation of genes controlling cell proliferation and division. Dysregulation of gene expression is involved in tumorigenesis and aberrant activation of histone deacetylases has been reported in several types of cancer. Moreover, there is growing body of evidence showing that acetylation is widely involved in non-histone proteins to impact their roles in various cellular processes including tumorigenesis. As such, small molecular compounds inhibiting HAT or HDAC enzymatic activities have been developed and investigated for therapeutic purpose. Here we review the recent progress in our understanding of protein acetylation and discuss the therapeutic potential of targeting the acetylation signaling pathway in cancer.
Topics: Humans; Acetylation; Histone Deacetylase Inhibitors; Histone Deacetylases; Protein Processing, Post-Translational; Neoplasms; Proteins; Signal Transduction; Carcinogenesis
PubMed: 33705871
DOI: 10.1016/j.semcancer.2021.03.001