The redox8208;active fungal metabolite, gliotoxin, induces transcriptional remodelling in Saccharomyces cerevisiae

Ref ID: 18448

Author:

Stephen Hammel, Jennifer O,Brien, Stephen Carberry, David Fitzpatrick, Sean Doyle, Gary W. Jones

Author address:

Yeast Genetics Lab, National University of Ireland, Maynooth, Ireland.

Full conference title:

11 th European Conference on Fungal Genetics

Abstract:

The opportunistic pathogen Aspergillus fumigatus is the cause of invasive aspergillosis and has a significant impact
on mortality of immunocomprised patients. The redox active, non8208;ribosomal peptide, gliotoxin, which is highly
toxic towards animal cells and fungi is produced by this organism however the precise mechanism of its anti8208;fungal
activity remains to be elucidated. We have identified and characterised proteins and genes that are up8208; or down8208; 
regulated in A. fumigatus and Saccharomyces cerevisiae in response to gliotoxin exposure. Proteomic analysis of A.
fumigatus exposed to gliotoxin (14 micro g/ml) revealed de novo expression of a short chain dehydrogenase,
eukaryotic translation elongation factor  β 1 and Cu/Zn super oxide dismutase; as well as a reduction in the
expression of the mycelial catalase AFUA_6G10660 was observed.
To assess the effects on global gene expression in Saccharomyces cerevisiaefollowing exposure to gliotoxin we
applied RNAseq technology. Exposure to 16 or 64 µg/ml gliotoxin caused up8208;  and down8208;regulation of genes
involved in sulphur and carbohydrate metabolism and oxidative stress resistance.
A candidate gene approach identified S. cerevisiae mutants that exhibited altered sensitivity to gliotoxin exposure.
Strains were chosen, based upon proteomic data which identified proteins showing induction/repression in A.
fumigatus following exposure to gliotoxin. In contrast to a previous study that screened a S. cerevisiae gene
deletions, we identified that deletion of the  γ 8208;glutamylcysteine synthase 1 gene (GSH1), confered resistance to
gliotoxin (16 µg/ml) compared to wild type yeast strains. Also, mutants which lacked either the Cu/Zn superoxide
dismutase gene (SOD1) or the Yeast activating protein (YAP1) gene resulted in hypersensitivity in the presence of
gliotoxin compared to wild type strain. No growth difference was observed when using 916;CTT1, 916;GSH2 or 916;GLR1.
Our data indicates that exposure to gliotoxin causes a complex in vivo transcriptional remodelling altering the
expression of genes involved in metabolic pathways, while also appearing to induce oxidative stress in fungal cells.

Abstract Number: PR1.6

Conference Year: 2012

Link to conference website: http://www.ecfg.info/images/Abstract_Book_Electronic.pdf

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