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Molecular Neurodegeneration Jul 2023Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease...
BACKGROUND
Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood.
METHODS
We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice.
RESULTS
We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner.
CONCLUSION
ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Alzheimer Disease; Cognition; Disease Models, Animal; Histones; Acetate-CoA Ligase
PubMed: 37438762
DOI: 10.1186/s13024-023-00625-4 -
Journal of the American Chemical Society Jul 2023With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully...
With advances in chemically induced proximity technologies, heterobifunctional modalities such as proteolysis targeting chimeras (PROTACs) have been successfully advanced to clinics for treating cancer. However, pharmacologic activation of tumor-suppressor proteins for cancer treatment remains a major challenge. Here, we present a novel tylation rgeting himera (AceTAC) strategy to acetylate the p53 tumor suppressor protein. We discovered and characterized the first p53Y220C AceTAC, MS78, which recruits histone acetyltransferase p300/CBP to acetylate the p53Y220C mutant. MS78 effectively acetylated p53Y220C lysine 382 (K382) in a concentration-, time-, and p300-dependent manner and suppressed proliferation and clonogenicity of cancer cells harboring the p53Y220C mutation with little toxicity in cancer cells with wild-type p53. RNA-seq studies revealed novel p53Y220C-dependent upregulation of TRAIL apoptotic genes and downregulation of DNA damage response pathways upon acetylation induced by MS78. Altogether, the AceTAC strategy could provide a generalizable platform for targeting proteins, such as tumor suppressors, via acetylation.
Topics: Acetylation; Humans; Cell Line, Tumor; Tumor Suppressor Protein p53; Mutation; Models, Molecular; Protein Processing, Post-Translational; Protein Structure, Tertiary
PubMed: 37365684
DOI: 10.1021/jacs.3c04640 -
Expert Review of Proteomics Feb 2019Acetylation is a widely occurring post-translational modification (PTM) of proteins that plays a crucial role in many cellular physiological and pathological processes.... (Review)
Review
Acetylation is a widely occurring post-translational modification (PTM) of proteins that plays a crucial role in many cellular physiological and pathological processes. Over the last decade, acetylation analyses required the development of multiple methods to target individual acetylated proteins, as well as to cover a broader description of acetylated proteins that comprise the acetylome. Areas covered: This review discusses the different types of acetylation (N-ter/K-/O-acetylation) and then describes some major strategies that have been reported in the literature to detect, enrich, identify and quantify protein acetylation. The review highlights the advantages and limitations of these strategies, to guide researchers in designing their experimental investigations and analysis of protein acetylation. Finally, this review highlights the main applications of acetylomics (proteomics based on mass spectrometry) for understanding physiological and pathological conditions. Expert opinion: Recent advances in acetylomics have enhanced knowledge of the biological and pathological roles of protein acetylation and the acetylome. Besides, radiolabeling and western blotting remain also techniques-of-choice for targeted protein acetylation. Future challenges in acetylomics to analyze the N-ter and K-acetylome will most likely require enrichment/fractionation, MS instrumentation and bioinformatics. Challenges also remain to identify the potential biological roles of O-acetylation and cross-talk with other PTMs.
Topics: Acetylation; Mass Spectrometry; Protein Processing, Post-Translational; Proteome; Proteomics
PubMed: 30580641
DOI: 10.1080/14789450.2019.1559061 -
Nature Communications Mar 2022Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic...
Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
Topics: Acetylation; Amyotrophic Lateral Sclerosis; DNA-Binding Proteins; Humans; Lysine; Protein Aggregation, Pathological; Protein Processing, Post-Translational; RNA; Sirtuin 1
PubMed: 35264561
DOI: 10.1038/s41467-022-28822-7 -
Journal of Proteomics Jan 2017Lysine acetylation is a reversible modification controlled by two groups of enzymes: lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Acetylated lysine... (Review)
Review
Lysine acetylation is a reversible modification controlled by two groups of enzymes: lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Acetylated lysine residues are recognized by bromodomains, a family of evolutionarily conserved domains. The use of high-resolution mass spectrometry-based proteomics, in combination with the enrichment of acetylated peptides through immunoprecipitation with anti-acetyl-lysine antibodies, has expanded the number of acetylated proteins from histones and a few nuclear proteins to more than 2000 human proteins. Because acetylation targets almost all cellular processes, this modification has been associated with cancer. Several KATs, KDACs and bromodomain-containing proteins have been linked to cancer development. Many small molecules targeting some of these proteins have been or are being tested as potential cancer therapies. The stoichiometry of lysine acetylation has not been explored in cancer, representing a promising field in which to increase our knowledge of how this modification is affected in cancer. In this review, we will focus on the strategies that can be used to go deeper in the characterization of the protein lysine acetylation emphasizing in cancer research.
Topics: Acetylation; Humans; Lysine; Neoplasms; Nuclear Proteins; Protein Processing, Post-Translational; Proteomics
PubMed: 27746255
DOI: 10.1016/j.jprot.2016.10.003 -
Proteomics Aug 2011Protein acetylation plays a critical regulatory role in eukaryotes but until recently its significance and function in bacteria and the archaea were obscure. It is now... (Review)
Review
Protein acetylation plays a critical regulatory role in eukaryotes but until recently its significance and function in bacteria and the archaea were obscure. It is now clear, however, that prokaryotes have the capacity to acetylate both the α-amino groups of N-terminal residues and the ε-amino groups of lysine side chains. In this review, we bring together information indicating that such acetylation is widespread and that it is likely to regulate fundamental cellular processes. We particularly focus on lysine acetylation, which recent studies show can occur in proteins involved in transcription, translation, pathways associated with central metabolism and stress responses. Intriguingly, specific acetylated lysine residues map to critical regions in the three-dimensional structures of key proteins, e.g. to active sites or to surfaces that dock with other major cellular components. Like phosphorylation, acetylation appears to be an ancient reversible modification that can be present at multiple sites in proteins, thereby potentially producing epigenetic combinatorial complexity. It may be particularly important in regulating central metabolism in prokaryotes due to the requirement for acetyl-CoA and NAD(+) for protein acetyltransferases and Sir2-type deacetylases, respectively.
Topics: Acetylation; Acetyltransferases; Archaea; Archaeal Proteins; Bacteria; Bacterial Proteins; Lysine; Metabolic Networks and Pathways
PubMed: 21674803
DOI: 10.1002/pmic.201000812 -
Science's STKE : Signal Transduction... Aug 2004In 1966, the histone was identified as the first protein subject to reversible acetylation. The ensuing 30 years of research on histone acetylation has been critical for... (Review)
Review
In 1966, the histone was identified as the first protein subject to reversible acetylation. The ensuing 30 years of research on histone acetylation has been critical for elucidating how gene transcription and chromatin remodeling are regulated at the molecular level. This central focus on histones, however, has also restricted our understanding of reversible acetylation, and therefore the enzymes that catalyze this reaction, to cellular processes predominantly associated with chromatin. The study of reversible acetylation has become more or less synonymous with histone acetylation. Recent developments-including increased ability to detect acetylated proteins, the characterization of novel acetyltransferases and deacetylases, and the identification of specific inhibitors for these enzymes-have revealed that this histone-central paradigm probably reflects only a fraction of the cellular processes regulated by reversible acetylation. New studies have uncovered unexpected roles for reversible acetylation in many diverse areas, thereby establishing protein acetylation as a highly versatile signaling modification that has functions beyond gene transcription and chromatin remodeling.
Topics: Acetylation; Lysine
PubMed: 15304664
DOI: 10.1126/stke.2452004pe42 -
Nature Communications Oct 2023Lysine acetylation has been discovered in thousands of non-histone human proteins, including most metabolic enzymes. Deciphering the functions of acetylation is key to...
Lysine acetylation has been discovered in thousands of non-histone human proteins, including most metabolic enzymes. Deciphering the functions of acetylation is key to understanding how metabolic cues mediate metabolic enzyme regulation and cellular signaling. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is acetylated on multiple lysine residues. Using site-specifically acetylated G6PD, we show that acetylation can activate (AcK89) and inhibit (AcK403) G6PD. Acetylation-dependent inactivation is explained by structural studies showing distortion of the dimeric structure and active site of G6PD. We provide evidence for acetylation-dependent K95/97 ubiquitylation of G6PD and Y503 phosphorylation, as well as interaction with p53 and induction of early apoptotic events. Notably, we found that the acetylation of a single lysine residue coordinates diverse acetylation-dependent processes. Our data provide an example of the complex roles of acetylation as a posttranslational modification that orchestrates the regulation of enzymatic activity, posttranslational modifications, and apoptotic signaling.
Topics: Humans; Lysine; Acetylation; Protein Processing, Post-Translational
PubMed: 37798264
DOI: 10.1038/s41467-023-41895-2 -
Trends in Biochemical Sciences Mar 2016Reversible protein acetylation is a major regulatory mechanism for controlling protein function. Through genetic manipulations, dietary perturbations, and new proteomic... (Review)
Review
Reversible protein acetylation is a major regulatory mechanism for controlling protein function. Through genetic manipulations, dietary perturbations, and new proteomic technologies, the diverse functions of protein acetylation are coming into focus. Protein acetylation in mitochondria has taken center stage, revealing that 63% of mitochondrially localized proteins contain lysine acetylation sites. We summarize the field and discuss salient topics that cover spurious versus targeted acetylation, the role of SIRT3 deacetylation, nonenzymatic acetylation, and molecular models for regulatory acetylations that display high and low stoichiometry.
Topics: Acetylation; Mitochondria; Proteins
PubMed: 26822488
DOI: 10.1016/j.tibs.2015.12.006 -
Acetylation of Lactate Dehydrogenase Negatively Regulates the Acidogenicity of Streptococcus mutans.MBio Oct 2022Lysine acetylation, a ubiquitous and dynamic regulatory posttranslational modification (PTM), affects hundreds of proteins across all domains of life. In bacteria,...
Lysine acetylation, a ubiquitous and dynamic regulatory posttranslational modification (PTM), affects hundreds of proteins across all domains of life. In bacteria, lysine acetylation can be found in many essential pathways, and it is also crucial for bacterial virulence. However, the biological significance of lysine acetylation events to bacterial virulence factors remains poorly characterized. In Streptococcus mutans, the acetylome profiles help identify several lysine acetylation sites of lactate dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactic acid, causing the deterioration of teeth. We investigated the regulatory mechanism of LDH acetylation and characterized the effect of LDH acetylation on its function. We overexpressed the 15 Gcn5 -acetyltransferases (GNAT) family members in S. mutans and showed that the acetyltransferase ActA impaired its acidogenicity by acetylating LDH. Additionally, enzymatic acetyltransferase reactions demonstrated that purified ActA could acetylate LDH , and 10 potential lysine acetylation sites of LDH were identified by mass spectrometry, 70% of which were also detected . We further demonstrated that the lysine acetylation of LDH inhibited its enzymatic activity, and a subsequent rat caries model showed that ActA impaired the cariogenicity of S. mutans. Collectively, we demonstrated that ActA, the first identified and characterized acetyltransferase in S. mutans, acetylated the LDH enzymatically and inhibited its enzymatic activity, thereby providing a starting point for the further analysis of the biological significance of lysine acetylation in the virulence of S. mutans. Lysine acetylation, a dynamic regulatory posttranslational modification, remains poorly characterized in bacteria. Hundreds of proteins have been identified to be acetylated in bacteria, with advances made in acetylome analyses. However, the regulatory mechanisms and functional significance of the majority of these acetylated proteins remain unclear. We analyzed the acetylome profiles of Streptococcus mutans and found that lactate dehydrogenase (LDH) contains several lysine acetylation sites. We also demonstrated that the acetyltransferase ActA, a member of the Gcn5 -acetyltransferases (GNAT) family in S. mutans, acetylated LDH, inhibited its enzymatic ability to catalyze the conversion of pyruvate to lactic acid, and impaired its cariogenicity in a rat caries model. Therefore, LDH acetylation might be a potential target that can be exploited in the design of novel therapeutics to prevent dental caries.
Topics: Rats; Animals; Acetylation; Streptococcus mutans; Lysine; L-Lactate Dehydrogenase; Dental Caries; Protein Processing, Post-Translational; Virulence Factors; Acetyltransferases; Lactic Acid; Pyruvates
PubMed: 36043788
DOI: 10.1128/mbio.02013-22