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Biochemical and Biophysical Research... Aug 2023The tumor suppressor p53 is involved in variety of cell progresses including cell cycle arrest, apoptosis, DNA repair, senescence, cell metabolism and ferroptosis. Here,...
The tumor suppressor p53 is involved in variety of cell progresses including cell cycle arrest, apoptosis, DNA repair, senescence, cell metabolism and ferroptosis. Here, we identified lncRNA SCARNA10 (Small Cajal Body-Specific RNA 10) as a novel cellular factor that interacts with the DNA binding domain (DBD) of p53. Upon binding the DBD of p53 and CREB-binding protein (CBP), SCARNA10 promotes the acetylation of p53, and activates p53-mediated transcriptional activation. Overexpress or knockdown SCARNA10 leads to up (or down)-regulation of p53-mediated transcriptional activation, whereas not affecting p53 protein levels. Moreover, SCARNA10 directly activates transcription by increasing the acetylation of p53 C-terminal domain (CTD) without affecting p53 phosphorylation at Ser15. These results indicate that SCARNA10 is a novel factor which regulates p53 acetylation-dependent transcriptional activity and tumor suppression.
Topics: Acetylation; Cell Cycle Checkpoints; Protein Processing, Post-Translational; Transcriptional Activation; Tumor Suppressor Protein p53; RNA
PubMed: 37262951
DOI: 10.1016/j.bbrc.2023.05.091 -
Cancer Letters Oct 2023Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors,...
Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorine-mediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance.
Topics: Humans; Mitochondrial Dynamics; Acetylation; Sirtuin 1; Colorectal Neoplasms; Isocitrate Dehydrogenase
PubMed: 37648148
DOI: 10.1016/j.canlet.2023.216364 -
Frontiers in Immunology 2024The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of... (Review)
Review
The innate immune system of insects can respond more swiftly and efficiently to pathogens based on previous experience of encountering antigens. The understanding of molecular mechanisms governing immune priming, a form of immune memory in insects, including its transgenerational inheritance, remains elusive. It is still unclear if the enhanced expression of immune genes observed in primed insects can persist and be regulated through changes in chromatin structure via epigenetic modifications of DNA or histones, mirroring observations in mammals. Increasing experimental evidence suggests that epigenetic changes at the level of DNA/RNA methylation and histone acetylation can modulate the activation of insects' immune responses to pathogen exposure. Moreover, transgenerational inheritance of certain epigenetic modifications in model insect hosts can influence the transmission of pre-programmed immune responses to the offspring, leading to the development of evolved resistance. Epigenetic research in model insect hosts is on the brink of significant progress in the mechanistic understanding of chromatin remodeling within innate immunity, particularly the direct relationships between immunological priming and epigenetic alterations. In this review, we discuss the latest discoveries concerning the involvement of DNA methylation and histone acetylation in shaping the development, maintenance, and inheritance of immune memory in insects, culminating in the evolution of resistance against pathogens.
Topics: Animals; Epigenesis, Genetic; Immunologic Memory; Insecta; DNA Methylation; Histones; Immunity, Innate; Chromatin Assembly and Disassembly; Acetylation
PubMed: 38915407
DOI: 10.3389/fimmu.2024.1397521 -
Molecular Immunology Aug 2023Global warming is changing the distribution of different pathogens around the globe, and humans are more susceptible to new or re-emerging infections. The human response... (Review)
Review
Global warming is changing the distribution of different pathogens around the globe, and humans are more susceptible to new or re-emerging infections. The human response to microbes is complex and involves different mechanisms of the immune system. Regulation of gene expression of immunity genes and of metabolism of immune cells are essential in this process. Both mechanisms could be regulated by protein lysine acetylation that will control chromatin structure affecting gene expression or key enzyme activity involved in cellular processes. Protein acetylation is crucial for the immunity and involves two families of enzymes: lysine acetyltransferases (KATs), which will promote protein acetylation, and lysine deacetylases (KDACs) that will reduce this modification. Lysine deacetylases are divided into Zinc-dependent or HDACs and NAD -dependent, or Sirtuins. These enzymes are in the nucleus, cytosol, and mitochondria of mammalian cells affecting different cellular pathways, such as metabolism, gene expression, DNA repair, cell proliferation, and apoptosis, opening the opportunity to explore these proteins as drug targets in different diseases, including cancer and neurodegenerative illness. Although widely explored in chronic diseases, very little is known about the role of Sirtuins during host response against microbes' infection. In this review we aim to explore the most recent literature evidencing a role for these enzymes during host responses to viruses, bacterial and protozoan infections, pointing out how these proteins can be manipulated by these pathogens to progress in the infection. Moreover, we will uncover the potential of host KDACs as therapeutic targets to prevent infections by activating effector immune functions.
Topics: Animals; Humans; Lysine; Sirtuins; Protein Processing, Post-Translational; Acetylation; Mammals
PubMed: 37437515
DOI: 10.1016/j.molimm.2023.06.010 -
Nature Communications Oct 2023PACS1 syndrome is a neurodevelopmental disorder (NDD) caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp (PACS1)). The mechanism by which PACS1 causes...
PACS1 syndrome is a neurodevelopmental disorder (NDD) caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp (PACS1)). The mechanism by which PACS1 causes PACS1 syndrome is unknown, and no curative treatment is available. Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity. Consequently, PACS1 reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization. The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs. Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex, suggesting that targeting PACS1/HDAC6 may be an effective therapy for PACS1 syndrome.
Topics: Humans; Mice; Animals; Histone Deacetylase 6; Histone Deacetylases; Tubulin; Neurons; Protein Processing, Post-Translational; Syndrome; Acetylation; Histone Deacetylase Inhibitors; Vesicular Transport Proteins
PubMed: 37848409
DOI: 10.1038/s41467-023-42176-8 -
Biochimica Et Biophysica Acta. Gene... Sep 2023Circadian rhythm is a roughly 24-h wake and sleep cycle that almost all of the organisms on the earth follow when they execute their biological functions and... (Review)
Review
Circadian rhythm is a roughly 24-h wake and sleep cycle that almost all of the organisms on the earth follow when they execute their biological functions and physiological activities. The circadian clock is mainly regulated by the transcription-translation feedback loop (TTFL), consisting of the core clock proteins, including BMAL1, CLOCK, PERs, CRYs, and a series of accessory factors. The circadian clock and the downstream gene expression are not only controlled at the transcriptional and translational levels but also precisely regulated at the post-translational modification level. Recently, it has been discovered that CLOCK exhibits lysine acetyltransferase activities and could acetylate protein substrates. Core clock proteins are also acetylated, thereby altering their biological functions in the regulation of the expression of downstream genes. Studies have revealed that many protein acetylation events exhibit oscillation behavior. However, the biological function of acetylation on circadian rhythm has only begun to explore. This review will briefly introduce the acetylation and deacetylation of the core clock proteins and summarize the proteins whose acetylation is regulated by CLOCK and circadian rhythm. Then, we will also discuss the crosstalk between lysine acetylation and the circadian clock or other post-translational modifications. Finally, we will briefly describe the possible future perspectives in the field.
Topics: CLOCK Proteins; Lysine; Acetylation; Circadian Rhythm; Protein Processing, Post-Translational
PubMed: 37453648
DOI: 10.1016/j.bbagrm.2023.194958 -
Protein Science : a Publication of the... Jan 2024Glucokinase (GK) catalyzes the phosphorylation of glucose to form glucose-6-phosphate as the substrate of glycolysis for energy production. Acetylation of lysine...
Glucokinase (GK) catalyzes the phosphorylation of glucose to form glucose-6-phosphate as the substrate of glycolysis for energy production. Acetylation of lysine residues in Escherichia coli GK has been identified at multiple sites by a series of proteomic studies, but the impact of acetylation on GK functions remains largely unknown. In this study, we applied the genetic code expansion strategy to produce site-specifically acetylated GK variants which naturally exist in cells. Enzyme assays and kinetic analyses showed that lysine acetylation decreases the GK activity, mostly resulting from acetylation of K214 and K216 at the entrance of the active site, which impairs the binding of substrates. We also compared results obtained from the glutamine substitution method and the genetic acetyllysine incorporation approach, showing that glutamine substitution is not always effective for mimicking acetylated lysine. Further genetic studies as well as in vitro acetylation and deacetylation assays were performed to determine acetylation and deacetylation mechanisms, which showed that E. coli GK could be acetylated by acetyl-phosphate without enzymes and deacetylated by CobB deacetylase.
Topics: Escherichia coli; Lysine; Glucokinase; Acetylation; Glutamine; Proteomics; Protein Processing, Post-Translational
PubMed: 37996965
DOI: 10.1002/pro.4845 -
Journal of Bone and Mineral Research :... Dec 2023CREB-binding protein (CBP) (CREBBP) and p300 (EP300) are multifunctional histone acetyltransferases (HATs) with extensive homology. Germline mutations of CBP or p300...
CREB-binding protein (CBP) (CREBBP) and p300 (EP300) are multifunctional histone acetyltransferases (HATs) with extensive homology. Germline mutations of CBP or p300 cause skeletal abnormalities in humans and mice. However, the precise roles of CBP/p300 in bone homeostasis remain elusive. Here, we report that conditional knockout of CBP or p300 in osteoblasts results in reduced bone mass and strength due to suppressed bone formation. The HAT activity is further confirmed to be responsible for CBP/p300-mediated osteogenesis using A-485, a selective inhibitor of CBP/p300 HAT. Mechanistically, CBP/p300 HAT governs osteogenic gene expression in part through transcriptional activation of β-catenin and inhibition of Stat1. Furthermore, acetylation of histone H3K27 and the transcription factor Foxo1 are demonstrated to be involved in CBP/p300 HAT-regulated β-catenin and Stat1 transcription, respectively. Taken together, these data identify acetyltransferases CBP/p300 as critical regulators that promote osteoblast differentiation and reveal an epigenetic mechanism responsible for maintaining bone homeostasis. © 2023 American Society for Bone and Mineral Research (ASBMR).
Topics: Animals; Humans; Mice; Acetylation; beta Catenin; CREB-Binding Protein; Histone Acetyltransferases; Osteogenesis; p300-CBP Transcription Factors; STAT1 Transcription Factor
PubMed: 37850815
DOI: 10.1002/jbmr.4925 -
Accounts of Chemical Research Feb 2024Acetylation plays a critical role in regulating eukaryotic transcription via the modification of histones. Beyond this well-documented function, a less explored...
Acetylation plays a critical role in regulating eukaryotic transcription via the modification of histones. Beyond this well-documented function, a less explored biological frontier is the potential for acetylation to modify and regulate the function of RNA molecules themselves. -Acetylcytdine (acC) is a minor RNA nucleobase conserved across all three domains of life (archaea, bacteria, and eukarya), a conservation that suggests a fundamental role in biological processes. Unlike many RNA modifications that are controlled by large enzyme families, almost all organisms catalyze acC using a homologue of human Nat10, an essential disease-associated acetyltransferase enzyme.A critical step in defining the fundamental functions of RNA modifications has been the development of methods for their sensitive and specific detection. This Account describes recent progress enabling the use of chemical sequencing reactions to map and quantify acC with single-nucleotide resolution in RNA. To orient readers, we first provide historical background of the discovery of acC and the enzymes that catalyze its formation. Next, we describe mechanistic experiments that led to the development of first- and second-generation sequencing reactions able to determine acC's position in a polynucleotide by exploiting the nucleobase's selective susceptibility to reduction by hydride donors. A notable feature of this chemistry, which may serve as a prototype for nucleotide resolution RNA modification sequencing reactions more broadly, is its ability to drive a penetrant and detectable gain of signal specifically at acC sites. Emphasizing practical applications, we present how this optimized chemistry can be integrated into experimental workflows capable of sensitive, transcriptome-wide analysis. Such readouts can be applied to quantitatively define the acC landscape across the tree of life. For example, in human cell lines and yeast, this method has uncovered that acC is highly selective, predominantly occupying dominant sites within rRNA (rRNA) and tRNA (tRNA). By contrast, when we extend these analyses to thermophilic archaea they identify the potential for much more prevalent patterns of cytidine acetylation, leading to the discovery of a role for this modification in adaptation to environmental stress. Nucleotide resolution analyses of acC have also allowed for the determination of structure-activity relationships required for short nucleolar RNA (snoRNA)-catalyzed acC deposition and the discovery of organisms with unexpectedly divergent tRNA and rRNA acetylation signatures. Finally, we share how these studies have shaped our approach to evaluating novel acC sites reported in the literature and highlight unanswered questions and new directions that set the stage for future research in the field.
Topics: Humans; Cytidine; Acetylation; RNA; RNA, Transfer; Saccharomyces cerevisiae; Archaea; Nucleotides
PubMed: 38226431
DOI: 10.1021/acs.accounts.3c00673 -
Viruses Jan 2024Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent... (Review)
Review
Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent infectious human diseases globally. IAV continues to challenge existing vaccines and antiviral drugs via its ability to evolve constantly. It is critical to identify the molecular determinants of IAV pathogenesis to understand the basis of flu severity in different populations and design improved antiviral strategies. In recent years, acetylation has been identified as one of the determinants of IAV pathogenesis. Acetylation was originally discovered as an epigenetic protein modification of histones. But, it is now known to be one of the ubiquitous protein modifications of both histones and non-histone proteins and a determinant of proteome complexity. Since our first observation in 2007, significant progress has been made in understanding the role of acetylation during IAV infection. Now, it is becoming clearer that acetylation plays a pro-IAV function via at least three mechanisms: (1) by reducing the host's sensing of IAV infection, (2) by dampening the host's innate antiviral response against IAV, and (3) by aiding the stability and function of viral and host proteins during IAV infection. In turn, IAV antagonizes the host deacetylases, which erase acetylation, to facilitate its replication. This review provides an overview of the research progress made on this subject so far and outlines research prospects for the significance of IAV-acetylation interplay.
Topics: Humans; Acetylation; Histones; Epigenesis, Genetic; Influenza A virus; Influenza, Human; Antiviral Agents
PubMed: 38257831
DOI: 10.3390/v16010131