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MBio Oct 2022is a woody edible-oil plant in China, and anthracnose occurs wherever it is grown, causing serious losses each year. We previously identified that the histone...
is a woody edible-oil plant in China, and anthracnose occurs wherever it is grown, causing serious losses each year. We previously identified that the histone acetyltransferase CfGcn5 orchestrates growth, development, and pathogenicity in , the major causal agent of anthracnose on . To elucidate the underlying mechanism, we conducted a transcriptome analysis and found that CfGcn5 is mainly involved in ribosomes, catalytic and metabolic processes, primary metabolism, and autophagy. In addition, we provided evidence showing that CfGcn5 serves as an autophagy repressor to mediate the expression of many autophagy-related genes () and undergoes degradation during autophagy. Moreover, we found that the and gene-deletion mutants had defects in mitosis and autophagy, resulting in their decreased appressoria formation rates and lower turgor pressure. These combined effects caused the failure of their appressoria functions and caused defects on their pathogenicity, revealing the importance of autophagy in pathogenicity. Taken together, our study illustrates that the autophagy repressor CfGcn5 undergoes degradation in order to regulate autophagy-dependent pathogenicity in . spp. is ranked in the top 10 plant fungal pathogens and serves as a model for the study of hemibiotrophic pathogens, but its molecular mechanisms of pathogenesis remain largely unknown. Among species of , causes anthracnose disease on more than 50 plants, such as pears, apples, and the important, edible-oil plant . We previously identified that the histone acetyltransferase CfGcn5 regulates growth, development, and pathogenicity in . To explore the underlying mechanisms, we performed comparative transcriptomic studies and found that CfGcn5 regulates global gene expression, including multiple autophagy-related genes ( genes). We revealed that CfGcn5 is an autophagy repressor that undergoes degradation during autophagy to govern pathogenicity. We also showed that the autophagy-related proteins CfAtg8 and CfAtg9 are required for full pathogenicity due to their regulatory functions in mitosis and autophagy. Our findings are important because we provide the first comprehensive characterization of autophagy as well as the relationship between acetylation and autophagy functioning in the pathogenesis of spp., which might offer new potential targets for the management of anthracnose disease.
Topics: Colletotrichum; Virulence; Histone Acetyltransferases; Plant Diseases; Phylogeny; Autophagy; Autophagy-Related Proteins
PubMed: 35975920
DOI: 10.1128/mbio.01956-22 -
The FEBS Journal Nov 2013Post-translational modification of proteins is ubiquitous and mediates many cellular processes, including intracellular localization, protein-protein interactions,... (Review)
Review
Post-translational modification of proteins is ubiquitous and mediates many cellular processes, including intracellular localization, protein-protein interactions, enzyme activity, transcriptional regulation and protein stability. While the role of phosphorylation as a key post-translational modification has been well studied, the more evolutionarily conserved post-translational modification acetylation has only recently attracted attention as a key regulator of cellular events. Protein acetylation has been largely studied in the context of its role in histone modification and gene regulation, where histones are modified by histone acetyltransferases to promote transcription. However, more recent acetylomic and biochemical studies have revealed that acetylation is mediated by a broader family of protein acetyltransferases. The recent structure determination of several protein acetyltransferases has provided a wealth of molecular information regarding structural features of protein acetyltransferases, their enzymatic mechanisms, their mode of substrate-specific recognition and their regulatory elements. In this review, we briefly describe what is known about non-histone protein substrates, but mainly focus on a few recent structures of protein acetyltransferases to compare and contrast them with histone acetyltransferases to better understand the molecular basis for protein recognition and modification by this family of protein modification enzymes.
Topics: Acetyl Coenzyme A; Acetylation; Acetyltransferases; Animals; Catalytic Domain; Histone Acetyltransferases; Humans; Models, Molecular; Molecular Structure; Protein Processing, Post-Translational; Proteins; Substrate Specificity
PubMed: 23742047
DOI: 10.1111/febs.12373 -
Cellular and Molecular Life Sciences :... May 2018Conserved from yeast to humans, Elongator is a protein complex implicated in multiple processes including transcription regulation, α-tubulin acetylation, and tRNA... (Review)
Review
Conserved from yeast to humans, Elongator is a protein complex implicated in multiple processes including transcription regulation, α-tubulin acetylation, and tRNA modification, and its defects have been shown to cause human diseases such as familial dysautonomia. Elongator consists of two copies of six core subunits (Elp1, Elp2, Elp3, Elp4, Elp5, and Elp6) that are organized into two subcomplexes: Elp1/2/3 and Elp4/5/6 and form a stable assembly of ~ 850 kDa in size. Although the catalytic subunit of Elongator is Elp3, which contains a radical S-adenosyl-L-methionine (SAM) domain and a putative histone acetyltransferase domain, the Elp4/5/6 subcomplex also possesses ATP-modulated tRNA binding activity. How at the molecular level, Elongator performs its multiple functions and how the different subunits regulate Elongator's activities remains poorly understood. Here, we provide an overview of the proposed functions of Elongator and describe how recent structural studies provide new insights into the mechanism of action of this multifunctional complex.
Topics: Animals; Histone Acetyltransferases; Humans; Peptide Elongation Factors; Protein Binding; Protein Subunits; RNA, Transfer; Transcription, Genetic
PubMed: 29332244
DOI: 10.1007/s00018-018-2747-6 -
International Journal of Molecular... Jan 2016Changes in chromatin structure and heritably regulating the gene expression by epigenetic mechanisms, such as histone post-translational modification, are involved in... (Review)
Review
Changes in chromatin structure and heritably regulating the gene expression by epigenetic mechanisms, such as histone post-translational modification, are involved in most cellular biological processes. Thus, abnormal regulation of epigenetics is implicated in the occurrence of various diseases, including cancer. Human MOF (males absent on the first) is a member of the MYST (Moz-Ybf2/Sas3-Sas2-Tip60) family of histone acetyltransferases (HATs). As a catalytic subunit, MOF can form at least two distinct multiprotein complexes (MSL and NSL) in human cells. Both complexes can acetylate histone H4 at lysine 16 (H4K16); however, the NSL complex possesses broader substrate specificity and can also acetylate histone H4 at lysines 5 and 8 (H4K5 and H4K8), suggesting the complexity of the intracellular functions of MOF. Silencing of MOF in cells leads to genomic instability, inactivation of gene transcription, defective DNA damage repair and early embryonic lethality. Unbalanced MOF expression and its corresponding acetylation of H4K16 have been found in certain primary cancer tissues, including breast cancer, medulloblastoma, ovarian cancer, renal cell carcinoma, colorectal carcinoma, gastric cancer, as well as non-small cell lung cancer. In this review, we provide a brief overview of MOF and its corresponding histone acetylation, introduce recent research findings that link MOF functions to tumorigenesis and speculate on the potential role that may be relevant to tumorigenic pathways.
Topics: Acetylation; Animals; Carcinogenesis; Gene Expression Regulation, Neoplastic; Histone Acetyltransferases; Histones; Humans; Protein Processing, Post-Translational
PubMed: 26784169
DOI: 10.3390/ijms17010099 -
Molecular & Cellular Proteomics : MCP Jul 2022MRG15/MORF4L1 is a highly conserved protein in eukaryotes that contains a chromodomain (CHD) recognizing methylation of lysine 36 on histone H3 (H3K36me3) in chromatin....
MRG15/MORF4L1 is a highly conserved protein in eukaryotes that contains a chromodomain (CHD) recognizing methylation of lysine 36 on histone H3 (H3K36me3) in chromatin. Intriguingly, it has been reported in the literature to interact with several different factors involved in chromatin modifications, gene regulation, alternative mRNA splicing, and DNA repair by homologous recombination. To get a complete and reliable picture of associations in physiological conditions, we used genome editing and tandem affinity purification to analyze the stable native interactome of human MRG15, its paralog MRGX/MORF4L2 that lacks the CHD, and MRGBP (MRG-binding protein) in isogenic K562 cells. We found stable interchangeable association of MRG15 and MRGX with the NuA4/TIP60 histone acetyltransferase/chromatin remodeler, Sin3B histone deacetylase/demethylase, ASH1L histone methyltransferase, and PALB2-BRCA2 DNA repair protein complexes. These associations were further confirmed and analyzed by CRISPR tagging of endogenous proteins and comparison of expressed isoforms. Importantly, based on structural information, point mutations could be introduced that specifically disrupt MRG15 association with some complexes but not others. Most interestingly, we also identified a new abundant native complex formed by MRG15/X-MRGBP-BRD8-EP400NL (EP400 N-terminal like) that is functionally similar to the yeast TINTIN (Trimer Independent of NuA4 for Transcription Interactions with Nucleosomes) complex. Our results show that EP400NL, being homologous to the N-terminal region of NuA4/TIP60 subunit EP400, creates TINTIN by competing for BRD8 association. Functional genomics indicate that human TINTIN plays a role in transcription of specific genes. This is most likely linked to the H4ac-binding bromodomain of BRD8 along the H3K36me3-binding CHD of MRG15 on the coding region of transcribed genes. Taken together, our data provide a complete detailed picture of human MRG proteins-associated protein complexes, which are essential to understand and correlate their diverse biological functions in chromatin-based nuclear processes.
Topics: Chromatin; Histone Acetyltransferases; Histones; Humans; Nucleosomes; Transcription Factors
PubMed: 35636729
DOI: 10.1016/j.mcpro.2022.100253 -
Advances in Experimental Medicine and... 2017Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, and mild to severe mental... (Review)
Review
Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, and mild to severe mental retardation (Rubinstein and Taybi, Am J Dis Child 105:588-608, 1963, Hennekam et al., Am J Med Genet Suppl 6:56-64, 1990). RSTS is caused by de novo mutations in epigenetics-associated genes, including the cAMP response element-binding protein (CREBBP), the gene-encoding protein referred to as CBP, and the EP300 gene, which encodes the p300 protein, a CBP homologue. Recent studies of the epigenetic mechanisms underlying cognitive functions in mice provide direct evidence for the involvement of nuclear factors (e.g., CBP) in the control of higher cognitive functions. In fact, a role for CBP in higher cognitive function is suggested by the finding that RSTS is caused by heterozygous mutations at the CBP locus (Petrij et al., Nature 376:348-351, 1995). CBP was demonstrated to possess an intrinsic histone acetyltransferase activity (Ogryzko et al., Cell 87:953-959, 1996) that is required for CREB-mediated gene expression (Korzus et al., Science 279:703-707, 1998). The intrinsic protein acetyltransferase activity in CBP might directly destabilize promoter-bound nucleosomes, facilitating the activation of transcription. Due to the complexity of developmental abnormalities and the possible genetic compensation associated with this congenital disorder, however, it is difficult to establish a direct role for CBP in cognitive function in the adult brain. Although aspects of the clinical presentation in RSTS cases have been extensively studied, a spectrum of symptoms found in RSTS patients can be accessed only after birth, and, thus, prenatal genetic tests for this extremely rare genetic disorder are seldom considered. Even though there has been intensive research on the genetic and epigenetic function of the CREBBP gene in rodents, the etiology of this devastating congenital human disorder is largely unknown.
Topics: Acetylation; Animals; Brain; CREB-Binding Protein; Cognition; Disease Models, Animal; E1A-Associated p300 Protein; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Genetic Association Studies; Histone Acetyltransferases; Histone Code; Histone Deacetylase Inhibitors; Humans; Invertebrates; Mammals; Memory; Models, Neurological; Mutation; Nerve Tissue Proteins; Protein Processing, Post-Translational; RNA, Long Noncoding; Rubinstein-Taybi Syndrome
PubMed: 28523540
DOI: 10.1007/978-3-319-53889-1_3 -
BMC Biology Jan 2022Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular...
BACKGROUND
Epigenetic regulation relies on the activity of enzymes that use sentinel metabolites as cofactors to modify DNA or histone proteins. Thus, fluctuations in cellular metabolite levels have been reported to affect chromatin modifications. However, whether epigenetic modifiers also affect the levels of these metabolites and thereby impinge on downstream metabolic pathways remains largely unknown. Here, we tested this notion by investigating the function of N-alpha-acetyltransferase 40 (NAA40), the enzyme responsible for N-terminal acetylation of histones H2A and H4, which has been previously implicated with metabolic-associated conditions such as age-dependent hepatic steatosis and calorie-restriction-mediated longevity.
RESULTS
Using metabolomic and lipidomic approaches, we found that depletion of NAA40 in murine hepatocytes leads to significant increase in intracellular acetyl-CoA levels, which associates with enhanced lipid synthesis demonstrated by upregulation in de novo lipogenesis genes as well as increased levels of diglycerides and triglycerides. Consistently, the increase in these lipid species coincide with the accumulation of cytoplasmic lipid droplets and impaired insulin signalling indicated by decreased glucose uptake. However, the effect of NAA40 on lipid droplet formation is independent of insulin. In addition, the induction in lipid synthesis is replicated in vivo in the Drosophila melanogaster larval fat body. Finally, supporting our results, we find a strong association of NAA40 expression with insulin sensitivity in obese patients.
CONCLUSIONS
Overall, our findings demonstrate that NAA40 affects the levels of cellular acetyl-CoA, thereby impacting lipid synthesis and insulin signalling. This study reveals a novel path through which histone-modifying enzymes influence cellular metabolism with potential implications in metabolic disorders.
Topics: Acetyl Coenzyme A; Animals; Drosophila melanogaster; Epigenesis, Genetic; Histone Acetyltransferases; Histones; Humans; Insulin; Lipids; Lipogenesis; Mice; N-Terminal Acetyltransferase D
PubMed: 35057804
DOI: 10.1186/s12915-021-01225-8 -
Current Opinion in Structural Biology Dec 2011Rtt109 (Regulator of Ty1 Transposition 109) is a fungal-specific histone acetyltransferase required for modification of histone H3 K9, K27 and K56. These acetylations... (Review)
Review
Rtt109 (Regulator of Ty1 Transposition 109) is a fungal-specific histone acetyltransferase required for modification of histone H3 K9, K27 and K56. These acetylations are associated with nascent histone H3 and play an integral role in replication-coupled and repair-coupled nucleosome assembly. Rtt109 is unique among acetyltransferases as it is activated by a histone chaperone; either Vps75 (Vacuolar Protein Sorting 75) or Asf1 (Anti-silencing Function 1). Recent biochemical, structural and genetic studies have shed light on the intricacies of this activation. It is now clear that Rtt109-Asf1 acetylates K56, while Rtt109-Vps75 acetylates K9 and K27. This reinforces that Asf1 and Vps75 activate Rtt109 via distinct molecular mechanisms. Structures of Rtt109-Vps75 further imply that Vps75 positions histone H3 in the Rtt109 active site. These structures however raise questions regarding the stoichiometry of the Rtt109-Vps75 complex. This has ramifications for determining the physiological Rtt109 substrate.
Topics: Catalytic Domain; Histone Acetyltransferases; Models, Molecular; Molecular Chaperones; Saccharomyces cerevisiae Proteins; Structure-Activity Relationship; Substrate Specificity
PubMed: 22023828
DOI: 10.1016/j.sbi.2011.09.005 -
Molecular Microbiology Jun 2021In eukaryotes, histone acetylation catalyzed by histone acetyltransferase (HAT) has been demonstrated to be critical for various physiological processes. However, the...
In eukaryotes, histone acetylation catalyzed by histone acetyltransferase (HAT) has been demonstrated to be critical for various physiological processes. However, the biological functions of HAT and the underlying mechanism by which HAT-regulated processes are involved in fungal development and virulence in the human opportunistic pathogen Aspergillus fumigatus remain largely unexplored. Here, we functionally characterized the roles of Rtt109 in A. fumigatus, an ortholog of Saccharomyces cerevisiae histone acetyltransferase Rtt109. In vivo and in vitro HAT assays revealed that AfRtt109 functions as a canonical histone acetyltransferase, acetylating lysines 9 and 56 of histone H3. Deletion of Afrtt109 leads to severe defects in vegetative growth, conidiation, and causes reduced virulence in the Galleria mellonella model, as well as hypersensitivity to genotoxic agents. Moreover, site-directed mutagenesis revealed that the conserved arginine residues R265 and R306 of Rtt109 are required for the H3K9 and H3K56 acetylation and virulence of A. fumigatus. Unexpectedly, R265E and R306E mutants did not exhibit any detectable phenotypic defects, implying that A. fumigatus Rtt109 regulates fungal development via histone acetylation-independent mechanisms. Together, our results revealed the critical role of fungal-specific HAT Rtt109 in regulating fungal development and virulence, and suggested that it may serve as a unique target for antifungal therapies.
Topics: Acetylation; Animals; Aspergillus fumigatus; DNA Damage; DNA Repair; Gene Deletion; Histone Acetyltransferases; Histones; Humans; Moths; Virulence
PubMed: 33300219
DOI: 10.1111/mmi.14665 -
Cells Apr 2023Histone modifications, as key chromatin regulators, play a pivotal role in the pathogenesis of several diseases, such as cancer. Acetylation, and more specifically... (Review)
Review
Histone modifications, as key chromatin regulators, play a pivotal role in the pathogenesis of several diseases, such as cancer. Acetylation, and more specifically lysine acetylation, is a reversible epigenetic process with a fundamental role in cell life, able to target histone and non-histone proteins. This epigenetic modification regulates transcriptional processes and protein activity, stability, and localization. Several studies highlight a specific role for HAT1 in regulating molecular pathways, which are altered in several pathologies, among which is cancer. HAT1 is the first histone acetyltransferase discovered; however, to date, its biological characterization is still unclear. In this review, we summarize and update the current knowledge about the biological function of this acetyltransferase, highlighting recent advances of HAT1 in the pathogenesis of cancer.
Topics: Humans; Chromatin; Histone Acetyltransferases; Histones; Neoplasms
PubMed: 37048148
DOI: 10.3390/cells12071075