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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 -
Nature Communications Dec 2022Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle...
Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.
Topics: Acetylation; Histones; Epigenesis, Genetic; Cell Nucleus; Mitochondria
PubMed: 36460681
DOI: 10.1038/s41467-022-35199-0 -
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 -
Redox Biology Jul 2022Sirtuin-1 (SIRT1) is a critical nuclear deacetylase that participates in a wide range of biological processes. We hereby employed quantitative acetyl-proteomics to...
Sirtuin-1 (SIRT1) is a critical nuclear deacetylase that participates in a wide range of biological processes. We hereby employed quantitative acetyl-proteomics to globally reveal the landscape of SIRT1-dependent acetylation in colorectal cancer (CRC) cells stimulated by specific SIRT1 inhibitor Inauhzin (INZ). We strikingly observed that SIRT1 inhibition enhances protein acetylation levels, with the multisite-acetylated proteins (acetyl sites >4/protein) mainly enriched in mitochondria. INZ treatment increases mitochondrial fission and depolarization in CRC cells. The acetylation of mitochondrial proteins promoted by SIRT1 inhibition prevents the recruitment of ubiquitin and LC3 for mitophagic degradation. We then found that, SIRT1 inhibition increases the acetylation of mitochondrial calcium uniporter (MCU) at residue K332, resulting in mitochondrial Ca overload and depolarization, and ultimately CRC apoptosis. Arginine substitution of the K332 (K332R) dramatically decreases the mitochondrial Ca influx, mitochondrial membrane potential loss and ROS burst induced by INZ. This finding uncovers a non-canonical role of SIRT1 in regulating mitochondrial function and implicates a possible way for anticancer intervention through SIRT1 inhibition.
Topics: Acetylation; Calcium; Cell Death; Mitochondria; Sirtuin 1
PubMed: 35636016
DOI: 10.1016/j.redox.2022.102334 -
Annual Review of Microbiology Sep 2019Acetylation is a posttranslational modification conserved in all domains of life that is carried out by -acetyltransferases. While acetylation can occur on -amino... (Review)
Review
Acetylation is a posttranslational modification conserved in all domains of life that is carried out by -acetyltransferases. While acetylation can occur on -amino groups, this review will focus on -acetylation of lysyl residues and how the posttranslational modification changes the cellular physiology of bacteria. Up until the late 1990s, acetylation was studied in eukaryotes in the context of chromatin maintenance and gene expression. At present, bacterial protein acetylation plays a prominent role in central and secondary metabolism, virulence, transcription, and translation. Given the diversity of niches in the microbial world, it is not surprising that the targets of bacterial protein acetyltransferases are very diverse, making their biochemical characterization challenging. The paradigm for acetylation in bacteria involves the acetylation of acetyl-CoA synthetase, whose activity must be tightly regulated to maintain energy charge homeostasis. While this paradigm has provided much mechanistic detail for acetylation and deacetylation, in this review we discuss advances in the field that are changing our understanding of the physiological role of protein acetylation in bacteria.
Topics: Acetylation; Acetyltransferases; Bacteria; Lysine; Protein Processing, Post-Translational
PubMed: 31091420
DOI: 10.1146/annurev-micro-020518-115526 -
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 -
Glycoconjugate Journal Jun 2023The structure and properties of a group of gangliosides modified by mild alkaline treatment are discussed. We will present the occurrence and the structure of... (Review)
Review
The structure and properties of a group of gangliosides modified by mild alkaline treatment are discussed. We will present the occurrence and the structure of gangliosides carrying the N-acetyneuraminic acid O-acetylated in position 9, the Neu5,9Ac, and of gangliosides carrying a sialic acid that forms a lactone ring. Starting from biochemical data we will discuss the possible biochemical role played by these gangliosides in the processes of cell signaling and maintenance of brain functions.
Topics: Gangliosides; N-Acetylneuraminic Acid; Sialic Acids; Acetylation
PubMed: 36695939
DOI: 10.1007/s10719-023-10103-0 -
Nature Communications Sep 2022Covalent attachment of ubiquitin (Ub) to proteins is a highly versatile posttranslational modification. Moreover, Ub is not only a modifier but itself is modified by...
Covalent attachment of ubiquitin (Ub) to proteins is a highly versatile posttranslational modification. Moreover, Ub is not only a modifier but itself is modified by phosphorylation and lysine acetylation. However, the functional consequences of Ub acetylation are poorly understood. By generation and comprehensive characterization of all seven possible mono-acetylated Ub variants, we show that each acetylation site has a particular impact on Ub structure. This is reflected in selective usage of the acetylated variants by different E3 ligases and overlapping but distinct interactomes, linking different acetylated variants to different cellular pathways. Notably, not only electrostatic but also steric effects contribute to acetylation-induced changes in Ub structure and, thus, function. Finally, we provide evidence that p300 acts as a position-specific Ub acetyltransferase and HDAC6 as a general Ub deacetylase. Our findings provide intimate insights into the structural and functional consequences of Ub acetylation and highlight the general importance of Ub acetylation.
Topics: Acetylation; Acetyltransferases; Lysine; Protein Processing, Post-Translational; Static Electricity; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 36114200
DOI: 10.1038/s41467-022-33087-1 -
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 -
Current Biology : CB Dec 2017Among the different types of cytoskeletal components, microtubules arguably accumulate the greatest diversity of post-translational modifications (PTMs). Acetylation of... (Review)
Review
Among the different types of cytoskeletal components, microtubules arguably accumulate the greatest diversity of post-translational modifications (PTMs). Acetylation of lysine 40 (K40) of α-tubulin has received particular attention because it is the only tubulin PTM to be found in the lumen of microtubules: most other tubulin PTMs are found at the outer surface of the microtubule. As a consequence, the enzyme catalyzing K40 acetylation needs to penetrate the narrow microtubule lumen to find its substrate. Acetylated microtubules have been considered to be stable, long-lived microtubules; however, until recently, there was little information about whether the longevity of these microtubules is the cause or the consequence of acetylation. Current advances suggest that this PTM helps the microtubule lattice to cope with mechanical stress, thus facilitating microtubule self-repair. These observations now shed new light on the structural integrity of microtubules, as well as on the mechanisms and biological functions of tubulin acetylation. Here, we discuss recent insights into how acetylation is generated in the lumen of microtubules, and how this 'hidden' PTM can control the properties and functions of microtubules.
Topics: Acetylation; Biomechanical Phenomena; Microtubules; Protein Processing, Post-Translational; Stress, Mechanical
PubMed: 29207274
DOI: 10.1016/j.cub.2017.10.044