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Nature Reviews. Molecular Cell Biology May 2022Lysine acetylation is a widespread and versatile protein post-translational modification. Lysine acetyltransferases and lysine deacetylases catalyse the addition or... (Review)
Review
Lysine acetylation is a widespread and versatile protein post-translational modification. Lysine acetyltransferases and lysine deacetylases catalyse the addition or removal, respectively, of acetyl groups at both histone and non-histone targets. In this Review, we discuss several features of acetylation and deacetylation, including their diversity of targets, rapid turnover, exquisite sensitivity to the concentrations of the cofactors acetyl-CoA, acyl-CoA and NAD, and tight interplay with metabolism. Histone acetylation and non-histone protein acetylation influence a myriad of cellular and physiological processes, including transcription, phase separation, autophagy, mitosis, differentiation and neural function. The activity of lysine acetyltransferases and lysine deacetylases can, in turn, be regulated by metabolic states, diet and specific small molecules. Histone acetylation has also recently been shown to mediate cellular memory. These features enable acetylation to integrate the cellular state with transcriptional output and cell-fate decisions.
Topics: Acetylation; Histones; Lysine; Lysine Acetyltransferases; Protein Processing, Post-Translational
PubMed: 35042977
DOI: 10.1038/s41580-021-00441-y -
Cell Death and Differentiation Jan 2022High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate...
High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.
Topics: Acetylation; HMGB1 Protein; Humans; Lactic Acid; Macrophages; Sepsis
PubMed: 34363018
DOI: 10.1038/s41418-021-00841-9 -
Molecular Aspects of Medicine Aug 2022Protein post-translational modifications (PTMs) profoundly influence protein functions and play crucial roles in essentially all cell biological processes. The diverse... (Review)
Review
Protein post-translational modifications (PTMs) profoundly influence protein functions and play crucial roles in essentially all cell biological processes. The diverse realm of PTMs and their crosstalk is linked to many critical signaling events involved in neoplastic transformation, carcinogenesis and metastasis. The pathological roles of various PTMs are implicated in all aspects of cancer hallmark functions, cancer metabolism and regulation of tumor microenvironment. Study of PTMs has become an important area in cancer research to understand cancer biology and discover novel biomarkers and therapeutic targets. With a limited scope, this review attempts to discuss some PTMs of high frequency with recognized importance in cancer biology, including phosphorylation, acetylation, glycosylation, palmitoylation and ubiquitination, as well as their implications in clinical applications. These protein modifications are among the most abundant PTMs and profoundly implicated in carcinogenesis.
Topics: Acetylation; Carcinogenesis; Humans; Neoplasms; Phosphorylation; Protein Processing, Post-Translational; Proteins; Tumor Microenvironment
PubMed: 35400524
DOI: 10.1016/j.mam.2022.101097 -
Biochimica Et Biophysica Acta. Reviews... Jan 2023Acetyl-CoA, as an important molecule, not only participates in multiple intracellular metabolic reactions, but also affects the post-translational modification of... (Review)
Review
Acetyl-CoA, as an important molecule, not only participates in multiple intracellular metabolic reactions, but also affects the post-translational modification of proteins, playing a key role in the metabolic activity and epigenetic inheritance of cells. Cancer cells require extensive lipid metabolism to fuel for their growth, while also require histone acetylation modifications to increase the expression of cancer-promoting genes. As a raw material for de novo lipid synthesis and histone acetylation, acetyl-CoA has a major impact on lipid metabolism and histone acetylation in cancer. More importantly, in cancer, acetyl-CoA connects lipid metabolism with histone acetylation, forming a more complex regulatory mechanism that influences cancer growth, proliferation, metastasis.
Topics: Humans; Histones; Acetyl Coenzyme A; Lipid Metabolism; Acetylation; Neoplasms; Protein Processing, Post-Translational
PubMed: 36403921
DOI: 10.1016/j.bbcan.2022.188837 -
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 -
Nature Communications Oct 2023Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in...
Most eukaryotic proteins are N-terminally acetylated, but the functional impact on a global scale has remained obscure. Using genome-wide CRISPR knockout screens in human cells, we reveal a strong genetic dependency between a major N-terminal acetyltransferase and specific ubiquitin ligases. Biochemical analyses uncover that both the ubiquitin ligase complex UBR4-KCMF1 and the acetyltransferase NatC recognize proteins bearing an unacetylated N-terminal methionine followed by a hydrophobic residue. NatC KO-induced protein degradation and phenotypes are reversed by UBR knockdown, demonstrating the central cellular role of this interplay. We reveal that loss of Drosophila NatC is associated with male sterility, reduced longevity, and age-dependent loss of motility due to developmental muscle defects. Remarkably, muscle-specific overexpression of UbcE2M, one of the proteins targeted for NatC KO-mediated degradation, suppresses defects of NatC deletion. In conclusion, NatC-mediated N-terminal acetylation acts as a protective mechanism against protein degradation, which is relevant for increased longevity and motility.
Topics: Male; Humans; Amino Acid Sequence; Acetylation; Longevity; Protein Processing, Post-Translational; Ubiquitins; Ubiquitin-Protein Ligases
PubMed: 37891180
DOI: 10.1038/s41467-023-42342-y -
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 -
Journal of Cell Science Jul 2023Most proteins receive an acetyl group at the N terminus while in their nascency as the result of modification by co-translationally acting N-terminal acetyltransferases... (Review)
Review
Most proteins receive an acetyl group at the N terminus while in their nascency as the result of modification by co-translationally acting N-terminal acetyltransferases (NATs). The N-terminal acetyl group can influence several aspects of protein functionality. From studies of NAT-lacking cells, it is evident that several cellular processes are affected by this modification. More recently, an increasing number of genetic cases have demonstrated that N-terminal acetylation has crucial roles in human physiology and pathology. In this Cell Science at a Glance and the accompanying poster, we provide an overview of the human NAT enzymes and their properties, substrate coverage, cellular roles and connections to human disease.
Topics: Humans; Acetylation; Acetyltransferases; N-Terminal Acetyltransferases; Protein Processing, Post-Translational; Proteins
PubMed: 37462250
DOI: 10.1242/jcs.260766 -
Autophagy Jun 2023RB1CC1/FIP200 is an essential macroautophagy/autophagy protein that plays an important role in a variety of biological and disease processes through its canonical...
RB1CC1/FIP200 is an essential macroautophagy/autophagy protein that plays an important role in a variety of biological and disease processes through its canonical autophagy-dependent and -independent functions. However, it remains largely unknown whether post-translational modifications could regulate RB1CC1 and its associated autophagy functions. Here, we report acetylation of several lysine residues of RB1CC1 by acetyltransferase CREBBP (CREB binding protein), with K276 as the major CREBBP acetylation site. K276 is also identified as a ubiquitination site by mass spectrometry, and acetylation at this site reduces ubiquitination of RB1CC1 to inhibit its ubiquitin-dependent degradation. We also find that RB1CC1 contains an N-terminal intrinsically disordered region (IDR) capable of forming liquid-liquid phase separation (LLPS) in vitro, which may drive formation of RB1CC1 puncta with LLPS properties in cells independent of SQSTM1/p62 and other autophagy receptors CALCOCO2/NDP52, NBR1, TAX1BP1 and OPTN. Mutational analysis shows that both K276 acetylation and the N-terminal IDR containing it are important for maintaining canonical autophagy function of RB1CC1 in breast cancer cells. Our findings demonstrate regulation of RB1CC1 by a new post-translational mechanism and suggest potential therapeutic application of inducing RB1CC1 degradation through blocking K276 acetylation in the treatment of cancer and other diseases. Baf-A1: bafilomycin A; CREBBP/CBP: CREB binding protein; CHX: cycloheximide; EP300/p300: E1A binding protein p300; FRAP: fluorescence recovery after photobleaching; HADCs: histone deacetylases; IDR: intrinsically disordered region; LLPS: liquid-liquid phase separation; KAT2A/GCN5: lysine acetyltransferase 2A; KAT2B/PCAF: lysine acetyltransferase 2B; KAT5/TIP60: lysine acetyltransferase 5; KAT8/MOF: lysine acetyltransferase 8; NAM: nicotinamide; PAS: phagophore assembly site; PEG-8000: polyethylene glycol 8000; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TSA: trichostatin A.
Topics: Autophagy; CREB-Binding Protein; Acetylation; Protein Processing, Post-Translational; Cell Cycle Proteins
PubMed: 36394358
DOI: 10.1080/15548627.2022.2148432