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Biomedicine & Pharmacotherapy =... Dec 2023Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves... (Review)
Review
Acetyl-coenzyme A (acetyl-CoA), an essential metabolite, not only takes part in numerous intracellular metabolic processes, powers the tricarboxylic acid cycle, serves as a key hub for the biosynthesis of fatty acids and isoprenoids, but also serves as a signaling substrate for acetylation reactions in post-translational modification of proteins, which is crucial for the epigenetic inheritance of cells. Acetyl-CoA links lipid metabolism with histone acetylation to create a more intricate regulatory system that affects the growth, aggressiveness, and drug resistance of malignancies such as glioblastoma, breast cancer, and hepatocellular carcinoma. These fascinating advances in the knowledge of acetyl-CoA metabolism during carcinogenesis and normal physiology have raised interest regarding its modulation in malignancies. In this review, we provide an overview of the regulation and cancer relevance of main metabolic pathways in which acetyl-CoA participates. We also summarize the role of acetyl-CoA in the metabolic reprogramming and stress regulation of cancer cells, as well as medical application of inhibitors targeting its dysregulation in therapeutic intervention of cancers.
Topics: Humans; Histones; Acetyl Coenzyme A; Signal Transduction; Lipid Metabolism; Glioblastoma; Acetylation
PubMed: 37864899
DOI: 10.1016/j.biopha.2023.115741 -
Nature Communications Mar 2024The properties of single microtubules within the microtubule network can be modulated through post-translational modifications (PTMs), including acetylation within the...
The properties of single microtubules within the microtubule network can be modulated through post-translational modifications (PTMs), including acetylation within the lumen of microtubules. To access the lumen, the enzymes could enter through the microtubule ends and at damage sites along the microtubule shaft. Here we show that the acetylation profile depends on damage sites, which can be caused by the motor protein kinesin-1. Indeed, the entry of the deacetylase HDAC6 into the microtubule lumen can be modulated by kinesin-1-induced damage sites. In contrast, activity of the microtubule acetylase αTAT1 is independent of kinesin-1-caused shaft damage. On a cellular level, our results show that microtubule acetylation distributes in an exponential gradient. This gradient results from tight regulation of microtubule (de)acetylation and scales with the size of the cells. The control of shaft damage represents a mechanism to regulate PTMs inside the microtubule by giving access to the lumen.
Topics: Acetylation; Kinesins; Microtubules; Acetylesterase; Protein Processing, Post-Translational
PubMed: 38448418
DOI: 10.1038/s41467-024-46379-5 -
Applied Biochemistry and Biotechnology Oct 2023Non-histone protein acetylation is involved in key cellular processes both in eukaryotes and prokaryotes. Acetylation in bacteria is used to modify proteins involved in...
Non-histone protein acetylation is involved in key cellular processes both in eukaryotes and prokaryotes. Acetylation in bacteria is used to modify proteins involved in metabolism and allow the bacteria to adapt to their environment. TTE (Thermoanaerobacter tengcongensis) is an anaerobic, thermophilic saccharolytic bacterium that grows at extreme temperature range between 50 and 80 ℃. The annotated TTE proteome contains less than 3000 proteins. We analyzed the proteome and acetylome of TTE using 2DLC-MS/MS (2-dimensional liquid chromatography mass spectrum). We evaluated the ability of mass spectrometry technology to cover a relatively small proteome as much as possible. And we also observed wide spread of acetylation in TTE, which changed under different temperatures. A total of 2082 proteins were identified, which accounts for about 82% of the database. A total of 2050 (~ 98%) proteins were quantified in at least one culture condition and 1818 proteins were quantified in all 4 conditions. The result also consisted 3457 acetylation sites corresponding to 827 distinct proteins, which covered 40% of the proteins identified. Bioinformatics analysis reported that proteins related to replication, recombination, repair, and extracellular structure cell wall biogenesis had more than half members acetylated, while energy production, carbohydrate transport, and metabolism related proteins were least acetylated. Our result suggested that acetylation affects the ATP-related energy metabolism and energy-dependent biosynthesis process. Comparing the enzymes related with lysine acetylation and acetyl-CoA (acetyl-coenzyme A) metabolism, we suggested that the acetylation of TTE took a non-enzymatic mechanism and affected by abundance of acetyl-CoA.
Topics: Proteome; Tandem Mass Spectrometry; Acetyl Coenzyme A; Acetylation; Protein Processing, Post-Translational
PubMed: 36809429
DOI: 10.1007/s12010-023-04361-9 -
Translational Oncology Jan 2024Adipocytes are derived from pluripotent mesenchymal stem cells and can develop into several cell types including adipocytes, myocytes, chondrocytes, and osteocytes.... (Review)
Review
Adipocytes are derived from pluripotent mesenchymal stem cells and can develop into several cell types including adipocytes, myocytes, chondrocytes, and osteocytes. Adipocyte differentiation is regulated by a variety of transcription factors and signaling pathways. Various epigenetic factors, particularly histone modifications, play key roles in adipocyte differentiation and have indispensable functions in altering chromatin conformation. Histone acetylases and deacetylases participate in the regulation of protein acetylation, mediate transcriptional and post-translational modifications, and directly acetylate or deacetylate various transcription factors and regulatory proteins. The adipocyte differentiation of stem cells plays a key role in various metabolic diseases. Cancer stem cells(CSCs) play an important function in cancer metastasis, recurrence, and drug resistance, and have the characteristics of stem cells. They are expressed in various cell lineages, including adipocytes. Recent studies have shown that cancer stem cells that undergo epithelial-mesenchymal transformation can undergo adipocytic differentiation, thereby reducing the degree of malignancy. This opens up new possibilities for cancer treatment. This review summarizes the regulation of acetylation during adipocyte differentiation, involving the functions of histone acetylating and deacetylating enzymes as well as non-histone acetylation modifications. Mechanistic studies on adipogenesis and acetylation during the differentiation of cancer cells into a benign cell phenotype may help identify new targets for cancer treatment.
PubMed: 37935080
DOI: 10.1016/j.tranon.2023.101815 -
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 -
Frontiers in Cellular and Infection... 2023Tuberculosis (TB) is a widespread infectious disease caused by (), which has been a significant burden for a long time. Post-translational modifications (PTMs) are... (Review)
Review
Tuberculosis (TB) is a widespread infectious disease caused by (), which has been a significant burden for a long time. Post-translational modifications (PTMs) are essential for protein function in both eukaryotic and prokaryotic cells. This review focuses on the contribution of protein acetylation to the function of and its infected macrophages. The acetylation of proteins plays a critical role in virulence, drug resistance, regulation of metabolism, and host anti-TB immune response. Similarly, the PTMs of host proteins induced by are crucial for the development, treatment, and prevention of diseases. Host protein acetylation induced by is significant in regulating host immunity against TB, which substantially affects the disease's development. The review summarizes the functions and mechanisms of acetyltransferase in virulence and drug resistance. It also discusses the role and mechanism of in regulating host protein acetylation and immune response regulation. Furthermore, the current scenario of isoniazid usage in therapy treatment is examined. Overall, this review provides valuable information that can serve as a preliminary basis for studying pathogenic research, developing new drugs, exploring in-depth drug resistance mechanisms, and providing precise treatment for TB.
Topics: Humans; Acetylation; Acetyltransferases; Mycobacterium tuberculosis; Protein Processing, Post-Translational; Tuberculosis; Macrophages
PubMed: 37560320
DOI: 10.3389/fcimb.2023.1218583 -
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 -
Biomedicine & Pharmacotherapy =... Sep 2023Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the... (Review)
Review
Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of histone and nonhistone crotonylation in reproduction, development, and disease. Although the regulatory enzyme systems and targets of crotonylation partially overlap with those of acetylation, the peculiar CC bond structure of crotonylation suggests that crotonylation may have specific biological functions. In this review, we summarize the latest research progress regarding crotonylation, especially its regulatory factors and relationship with diseases, which suggest further research directions for crotonylation and provide new ideas for developing disease intervention and treatment regimens.
Topics: Histones; Lysine; Acetylation; Protein Processing, Post-Translational
PubMed: 37392654
DOI: 10.1016/j.biopha.2023.115108 -
The Biochemical Journal Aug 2023Post-translational modifications (PTMs) provide a rapid response to stimuli, finely tuning metabolism and gene expression and maintain homeostasis. Advances in mass... (Review)
Review
Post-translational modifications (PTMs) provide a rapid response to stimuli, finely tuning metabolism and gene expression and maintain homeostasis. Advances in mass spectrometry over the past two decades have significantly expanded the list of known PTMs in biology and as instrumentation continues to improve, this list will surely grow. While many PTMs have been studied in detail (e.g. phosphorylation, acetylation), the vast majority lack defined mechanisms for their regulation and impact on cell fate. In this review, we will highlight the field of PTM research as it currently stands, discussing the mechanisms that dictate site specificity, analytical methods for their detection and study, and the chemical tools that can be leveraged to define PTM regulation. In addition, we will highlight the approaches needed to discover and validate novel PTMs. Lastly, this review will provide a starting point for those interested in PTM biology, providing a comprehensive list of PTMs and what is known regarding their regulation and metabolic origins.
Topics: Humans; Protein Processing, Post-Translational; Phosphorylation; Acetylation; Cell Differentiation; Homeostasis
PubMed: 37610048
DOI: 10.1042/BCJ20220251 -
Cell Death & Disease Aug 2023B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disorder with a dismal prognosis. The dysregulation of histone acetylation is of great...
B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disorder with a dismal prognosis. The dysregulation of histone acetylation is of great significance in the pathogenesis and progression of B-ALL. Regarded as a fundamental acetyltransferase gene, the role of HBO1 (lysine acetyltransferase 7/KAT7) in B-ALL has not been investigated. Herein, we found that HBO1 expression was elevated in human B-ALL cells and associated with poor disease-free survival. Strikingly, HBO1 knockdown inhibited viability, proliferation, and G1-S cycle progression in B-ALL cells, while provoking apoptosis. In contrast, ectopic overexpression of HBO1 enhanced cell viability and proliferation but inhibited apoptotic activation. The results of in vivo experiments also certificated the inhibitory effect of HBO1 knockdown on tumor growth. Mechanistically, HBO1 acetylated histone H3K14, H4K8, and H4K12, followed by upregulating CTNNB1 expression, resulting in activation of the Wnt/β-catenin signaling pathway. Moreover, a novel small molecule inhibitor of HBO1, WM-3835, potently inhibited the progression of B-ALL. Our data identified HBO1 as an efficacious regulator of CTNNB1 with therapeutic potential in B-ALL.
Topics: Humans; Acetylation; beta Catenin; Carcinogenesis; Histone Acetyltransferases; Histones; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Wnt Signaling Pathway
PubMed: 37542030
DOI: 10.1038/s41419-023-06019-0