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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 -
Cell Metabolism Jan 2024The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived...
The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.
Topics: Humans; Antioxidants; Isocitrate Dehydrogenase; Histones; Acetylation; T-Lymphocytes; Neoplasms; Mitochondria
PubMed: 38171332
DOI: 10.1016/j.cmet.2023.12.010 -
Nature Aug 2023Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation. The Rpd3 small (Rpd3S) complex recognizes histone H3...
Context-dependent dynamic histone modifications constitute a key epigenetic mechanism in gene regulation. The Rpd3 small (Rpd3S) complex recognizes histone H3 trimethylation on lysine 36 (H3K36me3) and deacetylates histones H3 and H4 at multiple sites across transcribed regions. Here we solved the cryo-electron microscopy structures of Saccharomyces cerevisiae Rpd3S in its free and H3K36me3 nucleosome-bound states. We demonstrated a unique architecture of Rpd3S, in which two copies of Eaf3-Rco1 heterodimers are asymmetrically assembled with Rpd3 and Sin3 to form a catalytic core complex. Multivalent recognition of two H3K36me3 marks, nucleosomal DNA and linker DNAs by Eaf3, Sin3 and Rco1 positions the catalytic centre of Rpd3 next to the histone H4 N-terminal tail for deacetylation. In an alternative catalytic mode, combinatorial readout of unmethylated histone H3 lysine 4 and H3K36me3 by Rco1 and Eaf3 directs histone H3-specific deacetylation except for the registered histone H3 acetylated lysine 9. Collectively, our work illustrates dynamic and diverse modes of multivalent nucleosomal engagement and methylation-guided deacetylation by Rpd3S, highlighting the exquisite complexity of epigenetic regulation with delicately designed multi-subunit enzymatic machineries in transcription and beyond.
Topics: Acetylation; Cryoelectron Microscopy; DNA, Fungal; Epigenesis, Genetic; Histones; Lysine; Nucleosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Methylation; Multiprotein Complexes
PubMed: 37468628
DOI: 10.1038/s41586-023-06349-1 -
Nature Communications Dec 2023Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two...
Full activation of the NLRP3 inflammasome needs two sequential signals: a priming signal, followed by a second, assembly signal. Several studies have shown that the two signals trigger post-translational modification (PTM) of NLRP3, affecting activity of the inflammasome, however, the PTMs induced by the second signal are less well characterized. Here, we show that the assembly signal involves acetylation of NLRP3 at lysine 24, which is important for the oligomerization and the actual assembly of NLRP3 without affecting its recruitment to dispersed trans-Golgi network (dTGN). Accordingly, NLRP3 inflammasome activation is impaired in NLRP3-K24R knock-in mice. We identify KAT5 as an acetyltransferase able to acetylate NLRP3. KAT5 deficiency in myeloid cells and pharmacological inhibition of KAT5 enzymatic activity reduce activation of the NLRP3 inflammasome, both in vitro and in vivo. Thus, our study reveals a key mechanism for the oligomerization and full activation of NLRP3 and lays down the proof of principle for therapeutic targeting of the KAT5-NLRP3 axis.
Topics: Mice; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Acetylation; Macrophages; Protein Processing, Post-Translational
PubMed: 38110429
DOI: 10.1038/s41467-023-44203-0 -
Nature Structural & Molecular Biology Nov 2023Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in...
Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in acetylation status, but how the large demands of acetyl-CoA are met is unclear. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to rapidly provide acetyl-CoA in response to DNA damage. We show that PDHE1α is quickly recruited to chromatin in a polyADP-ribosylation-dependent manner, which drives acetyl-CoA generation to support local chromatin acetylation around DSBs. This process increases the formation of relaxed chromatin to facilitate repair-factor loading, genome stability and cancer cell resistance to DNA-damaging treatments in vitro and in vivo. Indeed, we demonstrate that blocking polyADP-ribosylation-based PDHE1α chromatin recruitment attenuates chromatin relaxation and DSB repair efficiency, resulting in genome instability and restored radiosensitivity. These findings support a mechanism in which chromatin-associated PDHE1α locally generates acetyl-CoA to remodel the chromatin environment adjacent to DSBs and promote their repair.
Topics: Chromatin; Acetyl Coenzyme A; Acetylation; DNA Breaks, Double-Stranded; DNA Repair; DNA Damage; Pyruvates
PubMed: 37735618
DOI: 10.1038/s41594-023-01107-3 -
Gene Jan 2024Cancer is a major global health problem that disrupts the balance of normal cellular growth and behavior. Mounting evidence has shown that epigenetic modification,... (Review)
Review
Cancer is a major global health problem that disrupts the balance of normal cellular growth and behavior. Mounting evidence has shown that epigenetic modification, specifically N-terminal acetylation, play a crucial role in the regulation of cell growth and function. Acetylation is a co- or post-translational modification to regulate important cellular progresses such as cell proliferation, cell cycle progress, and energy metabolism. Recently, N-acetyltransferases (NATs), enzymes responsible for acetylation, regulate signal transduction pathway in various cancers including hepatocellular carcinoma, breast cancer, lung cancer, colorectal cancer and prostate cancer. In this review, we clarify the regulatory role of NATs in cancer progression, such as cell proliferation, metastasis, cell apoptosis, autophagy, cell cycle arrest and energy metabolism. Furthermore, the mechanism of NATs on cancer remains to be further studied, and few drugs have been developed. This provides us with a new idea that targeting acetylation, especially NAT-mediated acetylation, may be an attractive way for inhibiting cancer progression.
Topics: Male; Humans; Protein Processing, Post-Translational; Apoptosis; Neoplasms; Acetylation; Acetyltransferases
PubMed: 37783298
DOI: 10.1016/j.gene.2023.147866 -
Cell Death and Differentiation Aug 2023Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the...
Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the role of SLC25A51 in human disease, such as cancer, remains undefined. Here, we report that SLC25A51 is upregulated in multiple cancers, which promotes cancer cells proliferation. Loss of SLC25A51 elevates the mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, leading to the impairment of P5CS enzymatic activity, which is the key enzyme in proline biogenesis, and the reduction in proline contents. Notably, we find fludarabine phosphate, an FDA-approved drug, is able to bind with and inhibit SLC25A51 functions, causing mitochondrial NAD decrease and proteins hyperacetylation, which could further synergize with aspirin to reinforce the anti-tumor efficacy. Our study reveals that SLC25A51 is an attractive anti-cancer target, and provides a novel drug combination of fludarabine phosphate with aspirin as a potential cancer therapy strategy.
Topics: Animals; Humans; Acetylation; Proline; Mitochondria; Sirtuin 3; Homeostasis; Mammals
PubMed: 37419986
DOI: 10.1038/s41418-023-01185-2 -
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 -
International Journal of Molecular... Oct 2023Epigenetics play a crucial role in gene regulation and cellular processes. Most importantly, its dysregulation can contribute to the development of tumors. Epigenetic... (Review)
Review
Epigenetics play a crucial role in gene regulation and cellular processes. Most importantly, its dysregulation can contribute to the development of tumors. Epigenetic modifications, such as DNA methylation and histone acetylation, are reversible processes that can be utilized as targets for therapeutic intervention. DNA methylation inhibitors disrupt DNA methylation patterns by inhibiting DNA methyltransferases. Such inhibitors can restore normal gene expression patterns, and they can be effective against various forms of cancer. Histone deacetylase inhibitors increase histone acetylation levels, leading to altered gene expressions. Like DNA methylation inhibitors, histone methyltransferase inhibitors target molecules involved in histone methylation. Bromodomain and extra-terminal domain inhibitors target proteins involved in gene expression. They can be effective by inhibiting oncogene expression and inducing anti-proliferative effects seen in cancer. Understanding epigenetic modifications and utilizing epigenetic inhibitors will offer new possibilities for cancer research.
Topics: Humans; Histones; Neoplasms; DNA Methylation; Epigenesis, Genetic; Antineoplastic Agents; Histone Deacetylase Inhibitors; Acetylation
PubMed: 37834411
DOI: 10.3390/ijms241914964 -
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