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A. nidulans wild type strain transcriptome analysis upon 100 µM farnesol treatment.

ABSTRACT: Farnesol is a nonsterol isoprenoid produced by dephosphorylation of farnesyl pyrophosphate, a catabolite of the cholesterol biosynthetic pathway. These isoprenoids have been reported to inhibit proliferation and induce apoptosis in neoplastic cell lines as well as to be effective in chemotherapy in several in vivo cancer models. Recently, it was shown that farnesol triggers morphological features characteristic of apoptosis in the filamentous fungus Aspergillus nidulans. In order to investigate which pathways are involved under Farnesol treatment, we determined the transcriptional profile of A. nidulans wild type strain. Conidia were incubated at 37°C in complete medium for 16 hours and were esposed or not to 100 μM Farnesol for 2 hours. The mycelia were harvested by centrifugation and used for competitive microarray hybridizations. We detected differential regulation of genes involved in a variety of cellular processes whose specific modulation is likely to be implicated with A. nidulans adaptation to farnesol. We observed decreased mRNA abundance of several genes involved in RNA processing and modification, transcription, translation, ribosomal structure and biogenesis, amino acid transport and metabolism. Interestingly, several genes involved in the ergosterol biosynthesis (such as the homologues of erg4/24, 11A, -11B, -13, -25, and –28) have decreased mRNA accumulation and other genes encoding mitochondrial proteins [such as AN9103.3, AN4500.3, and AN5440.3, encoding the Apoptosis Inducing Factor (AIF)-like mitochondrial oxidoreductase, the mitochondrial ATPase inhibitor, and the cytochrome c peroxidase, respectively] have increased mRNA expression when A. nidulans was exposed to farnesol. We also observed as more expressed several genes encoding proteins involved in trehalose metabolism and chaperones. Keywords: farnesol effect

ORGANISM(S): Aspergillus nidulans

PROVIDER: GSE10712 | GEO | 2008/03/06

SECONDARY ACCESSION(S): PRJNA107593

REPOSITORIES: GEO

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Project description:Protein glycolysation is an essential posttranslational modification in eukaryotic cells. In pathogenic yeasts, it is involved in a large number of biological processes, such as protein folding quality control, cell viability and host/pathogen relationships. A link between protein glycosylation and apoptosis was established by the analysis of the phenotypes of oligosaccharyltransferase mutants in budding yeast. However, little is known about the contribution of glycosylation modifications to the adaptive response to apoptosis inducers. The cysteine protease metacaspase Mca1p plays a key role in the apoptotic response in Candida albicans triggered by the quorum sensing molecule farnesol. We subjected wild-type and mca1-deletion strains to farnesol stress and then studied the early phase of apoptosis release in quantitative glycoproteomics and glycomics experiments on cell-free extracts essentially devoid of cell walls. We identified and characterized 62 new glycosylated peptides with their glycan composition: 17 N-glycosylated, 45 O-glycosylated, and 81 additional sites of N-glycosylation. The glycosylated proteins were predicted as located mostly in the “membrane” and “cell wall” compartments, but they were also related to the “nucleus” and the “mitochondrial” compartments. They were found to be involved in the control of protein folding, cell wall integrity and cell cycle regulation. We showed a general increase in the O-glycosylation of proteins in the mca1 deletion strain after farnesol challenge. We identified 44 new putative protein substrates of the metacaspase in the glycoprotein fraction enriched on concanavalin A. Most of these substrates are involved in protein folding or protein resolubilization and in mitochondrial functions. We show here that key Mca1p substrates, such as Cdc48p or Ssb1p, involved in degrading misfolded glycoproteins and in the protein quality control system, are themselves differentially glycosylated. We found putative substrates, such as Bgl2p, Srb1p or Ugp1p, that are involved in the biogenesis of glycans. We validated as a substrate of Mca1p the endo-beta-1,3-glucanase Bgl2p which is involved in the incorporation of newly synthetized mannoproteins in the cell wall. Our findings highlight a new role of the metacaspase in amplifying cell death processes by affecting several critical protein quality control systems through the alteration of the protein glycosylation machinery.

Project description:David2008 - Genome-scale metabolic network of Aspergillus nidulans (iHD666) This model is described in the article: Analysis of Aspergillus nidulans metabolism at the genome-scale. David H, Ozçelik IS, Hofmann G, Nielsen J. BMC Genomics 2008; 9: 163 Abstract: BACKGROUND: Aspergillus nidulans is a member of a diverse group of filamentous fungi, sharing many of the properties of its close relatives with significance in the fields of medicine, agriculture and industry. Furthermore, A. nidulans has been a classical model organism for studies of development biology and gene regulation, and thus it has become one of the best-characterized filamentous fungi. It was the first Aspergillus species to have its genome sequenced, and automated gene prediction tools predicted 9,451 open reading frames (ORFs) in the genome, of which less than 10% were assigned a function. RESULTS: In this work, we have manually assigned functions to 472 orphan genes in the metabolism of A. nidulans, by using a pathway-driven approach and by employing comparative genomics tools based on sequence similarity. The central metabolism of A. nidulans, as well as biosynthetic pathways of relevant secondary metabolites, was reconstructed based on detailed metabolic reconstructions available for A. niger and Saccharomyces cerevisiae, and information on the genetics, biochemistry and physiology of A. nidulans. Thereby, it was possible to identify metabolic functions without a gene associated, and to look for candidate ORFs in the genome of A. nidulans by comparing its sequence to sequences of well-characterized genes in other species encoding the function of interest. A classification system, based on defined criteria, was developed for evaluating and selecting the ORFs among the candidates, in an objective and systematic manner. The functional assignments served as a basis to develop a mathematical model, linking 666 genes (both previously and newly annotated) to metabolic roles. The model was used to simulate metabolic behavior and additionally to integrate, analyze and interpret large-scale gene expression data concerning a study on glucose repression, thereby providing a means of upgrading the information content of experimental data and getting further insight into this phenomenon in A. nidulans. CONCLUSION: We demonstrate how pathway modeling of A. nidulans can be used as an approach to improve the functional annotation of the genome of this organism. Furthermore we show how the metabolic model establishes functional links between genes, enabling the upgrade of the information content of transcriptome data. This model is hosted on BioModels Database and identified by: MODEL1507180016. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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A. nidulans wild type strain transcriptome analysis upon 100 µM farnesol treatment.

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