Fungal acetylome comparative analysis identifies an essential role of acetylation in human fungal pathogen virulence
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ABSTRACT:
PROVIDER: PRJNA476875 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7384080_1.fastq.gz | Fastqsanger.gz | |||
| SRR7384080_2.fastq.gz | Fastqsanger.gz | |||
| SRR7384090_1.fastq.gz | Fastqsanger.gz | |||
| SRR7384090_2.fastq.gz | Fastqsanger.gz | |||
| SRR7384081_1.fastq.gz | Fastqsanger.gz |
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Project description:Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker’s yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae, we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes.
2019-04-26 | GSE116040 | GEO
Project description:Fungal pathogens cause deadly diseases in living organisms. Numerous studies suggest that lysine acetylation is a critical regulator in pathogenic fungi, but an in-depth and cross-species analysis of the acetylome in major pathogenic fungi is lacking, and our knowledge of the mechanism of acetylation in manipulating fungal pathogenicity is limited. Here, we show that lysine acetylation plays essential roles during cryptococcosis through modulating the gene expression of important virulence factors and the activity of key players in important pathways. We show that the Cryptococcus TOR pathway and translational elongation process are functionally regulated by acetylation via the HDAC and sirtuin families, respectively. Through comparative acetylome network analysis among pathogens and baker’s yeast, we demonstrate significant correlation between acetylation sites and virulence factors, indicating a unique selective pressure on lysine acetylation motifs in pathogenic fungi. These results provide a basis for understanding the regulation of fungal pathogenicity by posttranslational lysine acetylation.
2019-04-29 | PXD010354 | Pride
Project description:Lysine acetylation is critical in regulating important biological processes in many organisms, yet little is known about acetylome evolution and its contribution to phenotypic diversity. Here, we compare the acetylomes of baker's yeast and the three deadliest human fungal pathogens, Cryptococcus neoformans, Candida albicans, and Aspergillus fumigatus. Using mass spectrometry enriched for acetylated peptides together with public data from Saccharomyces cerevisiae, we show that fungal acetylomes are characterized by dramatic evolutionary dynamics and limited conservation in core biological processes. Notably, the levels of protein acetylation in pathogenic fungi correlate with their pathogenicity. Using gene knockouts and pathogenicity assays in mice, we identify deacetylases with critical roles in virulence and protein translation elongation. Finally, through mutational analysis of deactylation motifs we find evidence of positive selection at specific acetylation motifs in fungal pathogens. These results shed new light on the pathogenicity regulation mechanisms underlying the evolution of fungal acetylomes.
| S-EPMC6494858 | biostudies-other
Project description:Protein acetylation is a posttranslational modification that orchestrates gene regulation and various biological processes, such as fungal pathogenesis. One promising strategy for treating fungal infections is targeting the enzymes that regulate protein acetylation. Sirtuins, an NAD+-dependent lysine deacetylase, have been described as histone deacetylase and as regulators of secondary metabolism in various Aspergillus spp. However, the roles of sirtuin remain unclear. We employed a comprehensive set of experimental techniques, including gene deletion, phenotyping, in vivo virulence assays, metabolome analysis, transcriptome analysis, and acetylome analysis. Our findings reveal that sirtuins in A. fumigatus are intricately involved in crucial cellular processes such as cell wall integrity, secondary metabolite (SM) production, protease secretion, thermotolerance, and virulence. Notably, among the six sirtuins studied, AFSirE exerts a major influence on the phenotype of A. fumigatus. Furthermore, through acetylome analysis, we identified 42 and 260 proteins exhibiting differential acetylation in the AfSirE and SIRTko strains, respectively. Transcriptome data obtained from RNA sequencing (RNA-seq) demonstrated that sirtuins play a regulatory role in the expression of genes associated with SM production, cell wall component biosynthesis, and a variety of virulence factors.
2024-06-20 | PXD044964 | Pride
Project description:acylation also called S-palmitoylation is an important reversible protein post-translational modification in organisms. However, its function remains unknown in pathogenic fungi. Here, we found treatment of rice false fungus Ustilaginoidea virens with S-palmitoylation inhibitor 2-BP resulted in a significant decrease in fungal virulence and growth rate. Deletion of the S-acyltransferase proteins from U. virens indicated that two S-acyltransferases UvPfa3 and UvPfa4 were required for fungal virulence. Comprehensive identification of S-palmitoylation sites and proteins in U. virens revealed a total of 4089 S-palmitoylation sites were identified within 2192 proteins and S-palmitoylation proteins were involved in diverse biological processes. Interestingly, S-palmitoylation proteins were significantly enriched in mitogen-activated protein kinase (MAPK) pathway and MAP kinase UvSlt2 was confirmed to be a S-palmitoylation protein which was palmitoylated by UvPfa4. Mutations of S-palmitoylation sites in UvSlt2 resulted in significantly reduced fungal virulence and decreased kinase enzymatic activity and phosphorylation level. Molecular dynamics simulations demonstrated mutation of S-palmitoylation sites in UvSlt2 caused decreased hydrophobic solvent-accessible surface area, and thereby affected binding between the UvSlt2 enzyme and substrates. Taken together, S-palmitoylation promotes U. virens virulence through palmitoylating MAP kinase UvSlt2 by palmitoyltransferase UvPfa4 and enhancing enzymatic activity and phosphorylation level of the kinase, thereby increasing hydrophobic solvent-accessible surface area and binding activity between the UvSlt2 enzyme and its substrates. Our studies provide a framework for dissecting the biological functions of S-palmitoylation, and reveal an important role for S-palmitoylation in regulating virulence of pathogen.
2024-10-14 | PXD054433 | Pride
Project description:acylation also called S-palmitoylation is an important reversible protein post-translational modification in organisms. However, its function remains unknown in pathogenic fungi. Here, we found treatment of rice false fungus Ustilaginoidea virens with S-palmitoylation inhibitor 2-BP resulted in a significant decrease in fungal virulence and growth rate. Deletion of the S-acyltransferase proteins from U. virens indicated that two S-acyltransferases UvPfa3 and UvPfa4 were required for fungal virulence. Comprehensive identification of S-palmitoylation sites and proteins in U. virens revealed a total of 4089 S-palmitoylation sites were identified within 2192 proteins and S-palmitoylation proteins were involved in diverse biological processes. Interestingly, S-palmitoylation proteins were significantly enriched in mitogen-activated protein kinase (MAPK) pathway and MAP kinase UvSlt2 was confirmed to be a S-palmitoylation protein which was palmitoylated by UvPfa4. Mutations of S-palmitoylation sites in UvSlt2 resulted in significantly reduced fungal virulence and decreased kinase enzymatic activity and phosphorylation level. Molecular dynamics simulations demonstrated mutation of S-palmitoylation sites in UvSlt2 caused decreased hydrophobic solvent-accessible surface area, and thereby affected binding between the UvSlt2 enzyme and substrates. Taken together, S-palmitoylation promotes U. virens virulence through palmitoylating MAP kinase UvSlt2 by palmitoyltransferase UvPfa4 and enhancing enzymatic activity and phosphorylation level of the kinase, thereby increasing hydrophobic solvent-accessible surface area and binding activity between the UvSlt2 enzyme and its substrates. Our studies provide a framework for dissecting the biological functions of S-palmitoylation, and reveal an important role for S-palmitoylation in regulating virulence of pathogen.
2024-10-14 | PXD048216 | Pride
Project description:Protein lysine acetylation is recognized as an important reversible post translational modification in all domains of life. While its primary roles appear to reside in metabolic processes, lysine acetylation has also been implicated in regulating pathogenesis in bacteria. By now, several global lysine acetylome analyses have been carried out in various bacteria, but thus far there have been no reports of lysine acetylation taking place in the important human pathogen Vibrio cholerae. In this study, we analyzed the lysine acetylproteome of the human pathogen V. cholerae V52. By applying a combination of immuno-enrichment of acetylated peptides and high resolution mass spectrometry, we identified 3402 acetylation sites on 1240 proteins. Of the acetylated proteins, more than half were acetylated on two or more sites. As reported for other bacteria, we observed that many of the acetylated proteins were involved in metabolic and cellular processes and there was an over-representation of acetylated proteins involved in protein synthesis. Of interest, we demonstrated that many global transcription factors such as CRP, H-NS, IHF, Lrp and RpoN as well as transcription factors AphB, TcpP, PhoB, and ToxR, involved in direct regulation of virulence in V. cholerae were acetylated. In addition VAS effector proteins involved in type VI secretion were acetylated. The overall level of acetylation increased during growth and was higher in stationary phase. In conclusion, this is the first global protein lysine acetylome analysis of V. cholerae and should constitute a valuable resource for in-depth studies of the impact of lysine acetylation in pathogenesis and other cellular processes.
2018-01-02 | PXD008055 | Pride
Project description:The ability to grow at host temperature is a critical trait for most pathogenic microbes of humans. Thermally dimorphic fungal pathogens, including Histoplasma capsulatum, are a class of soil fungi that undergo a dramatic change in cell shape and virulence gene expression in response to host temperature. Here we elucidate a complex temperature-responsive network in H. capsulatum, which switches from an environmental filamentous form to a pathogenic yeast form. We dissect the circuit driven by three regulators that control yeast-phase growth, and demonstrate that these factors, including two deeply conserved Velvet family proteins of unknown function, associate with DNA. We identify and characterize a fourth regulator of this pathway, and define cis-acting motifs that recruit these transcription factors to a tightly interwoven network of temperature-responsive target genes. Our results provide the first comprehensive analysis of the complex transcriptional network that links temperature to morphology and virulence in thermally dimorphic fungi. This submission gives the chromatin immunoprecipitation results.
2013-06-14 | GSE47341 | GEO
Project description:Insertion Pool Sequencing Identifies Essential Fungal Virulence Factors in vivo
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Project description:The ability to grow at host temperature is a critical trait for most pathogenic microbes of humans. Thermally dimorphic fungal pathogens, including Histoplasma capsulatum, are a class of soil fungi that undergo a dramatic change in cell shape and virulence gene expression in response to host temperature. Here we elucidate a complex temperature-responsive network in H. capsulatum, which switches from an environmental filamentous form to a pathogenic yeast form. We dissect the circuit driven by three regulators that control yeast-phase growth, and demonstrate that these factors, including two deeply conserved Velvet family proteins of unknown function, associate with DNA. We identify and characterize a fourth regulator of this pathway, and define cis-acting motifs that recruit these transcription factors to a tightly interwoven network of temperature-responsive target genes. Our results provide the first comprehensive analysis of the complex transcriptional network that links temperature to morphology and virulence in thermally dimorphic fungi. This submission gives the expression profiling results.
2013-06-14 | GSE46939 | GEO