Schrettl, Markus and Carberry, Stephen and Kavanagh, Kevin and Haas, Hubertus and Jones, Gary W and O'Brien, Jennifer and Nolan, Aine and Stephens, John and Fenelon, Orla and Doyle, Sean
Self-Protection against Gliotoxin—A Component of the
Gliotoxin Biosynthetic Cluster, GliT, Completely Protects
Aspergillus fumigatus Against Exogenous Gliotoxin.
PLOS Pathogens, 6 (6).
Gliotoxin, and other related molecules, are encoded by multi-gene clusters and biosynthesized by fungi using nonribosomal biosynthetic mechanisms. Almost universally described in terms of its toxicity towards mammalian cells, gliotoxin has come to be considered as a component of the virulence arsenal of Aspergillus fumigatus. Here we show that deletion of a single gene, gliT, in the gliotoxin biosynthetic cluster of two A. fumigatus strains, rendered the organism highly sensitive to exogenous gliotoxin and completely disrupted gliotoxin secretion. Addition of glutathione to both A. fumigatus DgliT strains relieved gliotoxin inhibition. Moreover, expression of gliT appears to be independently regulated compared to all other
cluster components and is up-regulated by exogenous gliotoxin presence, at both the transcript and protein level. Upon gliotoxin exposure, gliT is also expressed in A. fumigatus DgliZ, which cannot express any other genes in the gliotoxin biosynthetic cluster, indicating that gliT is primarily responsible for protecting this strain against exogenous gliotoxin. GliT exhibits a gliotoxin reductase activity up to 9 mM gliotoxin and appears to prevent irreversible depletion of intracellular glutathione stores by reduction of the oxidized form of gliotoxin. Cross-species resistance to exogenous gliotoxin is acquired by A. nidulans and Saccharomyces cerevisiae, respectively, when transformed with gliT. We hypothesise that the primary role of gliotoxin may be as an antioxidant and that in addition to GliT functionality, gliotoxin secretion may be a
component of an auto-protective mechanism, deployed by A. fumigatus to protect itself against this potent biomolecule.
||This work was funded by an Enterprise Ireland grant (PC/2008/046), an EU Marie Curie award (MTKD-CT-2004-014436; Co-ordinator Dr Shirley O’Dea) and the Higher Education Authority Programme for Research in Third Level Institutions (HEA-PRTLI; Cycles 3 and 4). MALDI-ToF, HPLC, LC-ToF and LC-MS facilities were funded by the Health Research Board and the Higher Education Authority. Confocal microscopy facilities were funded by Science Foundation Ireland. JO’B was funded by SFI grant 08/RFP/BMT1439. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
||Gliotoxin—A; Gliotoxin Biosynthetic Cluster; GliT;
Aspergillus fumigatus; Exogenous Gliotoxin;
||Faculty of Science and Engineering > Biology
Dr. Sean Doyle
||22 Jun 2010 16:05
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