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Cell Stem Cell Apr 2021Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone...
Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone crotonylation remain almost completely unknown. Here we report that histone crotonylation is crucial for endoderm differentiation. We demonstrate that key crotonyl-coenzyme A (CoA)-producing enzymes are specifically induced in endodermal cells during differentiation of human embryonic stem cells (hESCs) in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Chemical enhancement of histone crotonylation promotes endoderm differentiation of hESCs, whereas deletion of crotonyl-CoA-producing enzymes reduces histone crotonylation and impairs meso/endoderm differentiation in vitro and in vivo. Our study uncovers a histone crotonylation-mediated mechanism that promotes endodermal commitment of pluripotent stem cells, which may have important implications for therapeutic strategies against a number of human diseases.
Topics: Acetylation; Animals; Cell Differentiation; Histones; Human Embryonic Stem Cells; Lysine; Mice; Protein Processing, Post-Translational
PubMed: 33450185
DOI: 10.1016/j.stem.2020.12.009 -
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 -
Translational Neurodegeneration May 2023The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system.... (Review)
Review
The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule (MT)-mediated axonal transport system. This mechanistically regulated system delivers cargos (proteins, mRNAs and organelles such as mitochondria) back and forth from the soma to the synapse. Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde (from the soma to the synapse) and retrograde (from the synapse to the soma) commute of the cargos, respectively. Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications (PTMs) of α- and β-tubulin heterodimers, core components constructing the MTs. Occurring within the lumen of MTs, K40 acetylation of α-tubulin via α-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible, which in turn promotes their lifespan. The movement of various motor proteins, including kinesin-1 (responsible for axonal mitochondrial commute), is enhanced by this PTM, and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions, including Alzheimer's disease and Parkinson's disease (PD). PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels. Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question, our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD. The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored. Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.
Topics: Humans; Tubulin; Parkinson Disease; Acetylation; Microtubules; Protein Processing, Post-Translational; Neurodegenerative Diseases
PubMed: 37150812
DOI: 10.1186/s40035-023-00354-0 -
Biomolecules Aug 2023Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can... (Review)
Review
Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
Topics: Mitochondria; Mitochondrial Membranes; Acetylation; Mitochondrial Dynamics; Mitochondrial Proteins
PubMed: 37627290
DOI: 10.3390/biom13081225 -
Molecular Cell Jan 2022Acetyl-CoA is a key intermediate situated at the intersection of many metabolic pathways. The reliance of histone acetylation on acetyl-CoA enables the coordination of...
Acetyl-CoA is a key intermediate situated at the intersection of many metabolic pathways. The reliance of histone acetylation on acetyl-CoA enables the coordination of gene expression with metabolic state. Abundant acetyl-CoA has been linked to the activation of genes involved in cell growth or tumorigenesis through histone acetylation. However, the role of histone acetylation in transcription under low levels of acetyl-CoA remains poorly understood. Here, we use a yeast starvation model to observe the dramatic alteration in the global occupancy of histone acetylation following carbon starvation; the location of histone acetylation marks shifts from growth-promoting genes to gluconeogenic and fat metabolism genes. This reallocation is mediated by both the histone deacetylase Rpd3p and the acetyltransferase Gcn5p, a component of the SAGA transcriptional coactivator. Our findings reveal an unexpected switch in the specificity of histone acetylation to promote pathways that generate acetyl-CoA for oxidation when acetyl-CoA is limiting.
Topics: Acetyl Coenzyme A; Acetylation; Gene Expression Regulation, Fungal; Gluconeogenesis; Glucose; Histone Acetyltransferases; Histone Deacetylases; Histones; Lipid Metabolism; Protein Processing, Post-Translational; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Trans-Activators
PubMed: 34995509
DOI: 10.1016/j.molcel.2021.12.015 -
Cells May 2023Cardiac fibrosis plays an essential role in the development of diastolic dysfunction and contributes to heart failure with preserved ejection fraction (HFpEF). Our...
Cardiac fibrosis plays an essential role in the development of diastolic dysfunction and contributes to heart failure with preserved ejection fraction (HFpEF). Our previous studies suggested Sirtuin 3 (SIRT3) as a potential target for cardiac fibrosis and heart failure. In the present study, we explored the role of SIRT3 in cardiac ferroptosis and its contribution to cardiac fibrosis. Our data showed that knockout of SIRT3 resulted in a significant increase in ferroptosis, with increased levels of 4-hydroxynonenal (4-HNE) and downregulation of glutathione peroxidase 4 (GPX-4) in the mouse hearts. Overexpression of SIRT3 significantly blunted ferroptosis in response to erastin, a known ferroptosis inducer, in H9c2 myofibroblasts. Knockout of SIRT3 resulted in a significant increase in p53 acetylation. Inhibition of p53 acetylation by C646 significantly alleviated ferroptosis in H9c2 myofibroblasts. To further explore the involvement of p53 acetylation in SIRT3-mediated ferroptosis, we crossed acetylated p53 mutant (p53) mice, which cannot activate ferroptosis, with SIRT3KO mice. SIRT3KO/p53 mice exhibited a significant reduction in ferroptosis and less cardiac fibrosis compared to SIRT3KO mice. Furthermore, cardiomyocyte-specific knockout of SIRT3 (SIRT3-cKO) in mice resulted in a significant increase in ferroptosis and cardiac fibrosis. Treatment of SIRT3-cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) led to a significant reduction in ferroptosis and cardiac fibrosis. We concluded that SIRT3-mediated cardiac fibrosis was partly through a mechanism involving p53 acetylation-induced ferroptosis in myofibroblasts.
Topics: Animals; Mice; Acetylation; Ferroptosis; Fibrosis; Heart Failure; Mice, Knockout; Myocytes, Cardiac; Sirtuin 3; Stroke Volume; Tumor Suppressor Protein p53
PubMed: 37408261
DOI: 10.3390/cells12101428 -
Nature Communications Sep 2023Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific...
Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific tau isoforms as disease-related tau filament structures. The molecular processes that determine isoform-specific deposition of tau are however enigmatic. Here we show that acetylation of tau discriminates its isoform-specific aggregation. We reveal that acetylation strongly attenuates aggregation of four-repeat tau protein, but promotes amyloid formation of three-repeat tau. We further identify acetylation of lysine 298 as a hot spot for isoform-specific tau aggregation. Solid-state NMR spectroscopy demonstrates that amyloid fibrils formed by unmodified and acetylated three-repeat tau differ in structure indicating that site-specific acetylation modulates tau structure. The results implicate acetylation as a critical regulator that guides the selective aggregation of three-repeat tau and the development of tau isoform-specific neurodegenerative diseases.
Topics: Humans; 14-3-3 Proteins; Acetylation; Alzheimer Disease; tau Proteins; Tauopathies
PubMed: 37739953
DOI: 10.1038/s41467-023-41672-1 -
Frontiers in Endocrinology 2022Polycystic ovary syndrome (PCOS) is a lifelong reproductive, metabolic, and psychiatric disorder that affects 5-18% of women, which is associated with a significantly... (Review)
Review
Polycystic ovary syndrome (PCOS) is a lifelong reproductive, metabolic, and psychiatric disorder that affects 5-18% of women, which is associated with a significantly increased lifetime risk of concomitant diseases, including type 2 diabetes, psychiatric disorders, and gynecological cancers. Posttranslational modifications (PTMs) play an important role in changes in protein function and are necessary to maintain cellular viability and biological processes, thus their maladjustment can lead to disease. Growing evidence suggests the association between PCOS and posttranslational modifications. This article mainly reviews the research status of phosphorylation, methylation, acetylation, and ubiquitination, as well as their roles and molecular mechanisms in the development of PCOS. In addition, we briefly summarize research and clinical trials of PCOS therapy to advance our understanding of agents that can be used to target phosphorylated, methylated, acetylated, and ubiquitinated PTM types. It provides not only ideas for future research on the mechanism of PCOS but also ideas for PCOS treatments with therapeutic potential.
Topics: Female; Humans; Polycystic Ovary Syndrome; Diabetes Mellitus, Type 2; Protein Processing, Post-Translational; Acetylation; Proteins
PubMed: 36277727
DOI: 10.3389/fendo.2022.1024320 -
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 Dec 2022N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the...
N-degron pathway plays an important role in the protein quality control and maintenance of cellular protein homeostasis. ZER1 and ZYG11B, the substrate receptors of the Cullin 2-RING E3 ubiquitin ligase (CRL2), recognize N-terminal (Nt) glycine degrons and participate in the Nt-myristoylation quality control through the Gly/N-degron pathway. Here we show that ZER1 and ZYG11B can also recognize small Nt-residues other than glycine. Specifically, ZER1 binds better to Nt-Ser, -Ala, -Thr and -Cys than to -Gly, while ZYG11B prefers Nt-Gly but also has the capacity to recognize Nt-Ser, -Ala and -Cys in vitro. We found that Nt-Ser, -Ala and -Cys undergo Nt-acetylation catalyzed by Nt-acetyltransferase (NAT), thereby shielding them from recognition by ZER1/ZYG11B in cells. Instead, ZER1/ZYG11B readily targets a selection of small Nt-residues lacking Nt-acetylation for degradation in NAT-deficient cells, implicating its role in the Nt-acetylation quality control. Furthermore, we present the crystal structures of ZER1 and ZYG11B bound to various small Nt-residues and uncover the molecular mechanism of non-acetylated substrate recognition by ZER1 and ZYG11B.
Topics: Ubiquitin-Protein Ligases; Protein Processing, Post-Translational; Acetylation; Myristic Acid; Glycine
PubMed: 36496439
DOI: 10.1038/s41467-022-35169-6