Genomewide Screening for Genes Associated with Gliotoxin Resistance and Sensitivity in
            <i>Saccharomyces cerevisiae</i>

Chamilos, Georgios; Lewis, Russell E.; Lamaris, Gregory A.; Albert, Nathaniel D.; Kontoyiannis, Dimitrios P.

doi:10.1128/aac.01393-07

Cited by 13 publications

(13 citation statements)

References 26 publications

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“…Moreover, the increased sensitivity to gliotoxin in S. cerevisiae Dyap1 implies that this gene is also essential to protect against gliotoxin-induced ROS. These data further the observations of Chamilos et al (2008) regarding the effects of gliotoxin on yeast mutants and future studies will explore the effects of gliotoxin on A. fumigatus Dyap1. Our observation that S. cerevisiae Dgsh1, severely deficient in GSH (Lee et al, 2001), exhibits greater resistance to gliotoxin than wild-type -and that complementation with GSH1 restores wild-type levels of gliotoxin sensitivity -further underpins our proposal that intracellular GSH levels play an important role in mediating gliotoxin cytotoxicity in fungi as has been noted in animals cells by Bernardo et al (2003).…”

Section: Discussionsupporting

confidence: 71%

“…Indeed, Cramer et al (2006) demonstrated that exogenous gliotoxin controlled the expression of the gli cluster in A. fumigatus and thereby regulated its own production. Chamilos et al (2008) studied the effect of gliotoxin on Saccharomyces cerevisiae, using a library of single-gene mutants (4787 strains), in an attempt to further elucidate mechanisms of gliotoxin cytotoxicity and identify novel drug targets in eukaryotic cells. Overall, 10 mutants exhibited increased resistance to gliotoxin while 3 were statistically more sensitive to exogenous gliotoxin, compared to wild-type.…”

Section: Introductionmentioning

confidence: 99%

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Gliotoxin effects on fungal growth: Mechanisms and exploitation

Carberry

Molloy

Hammel

et al. 2012

Fungal Genetics and Biology

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a b s t r a c tAlthough initially investigated for its antifungal properties, little is actually known about the effect of gliotoxin on Aspergillus fumigatus and other fungi. We have observed that exposure of A. fumigatus to exogenous gliotoxin (14 lg/ml), under gliotoxin-limited growth conditions, results in significant alteration of the expression of 27 proteins (up-and down-regulated >1.9-fold; p < 0.05) including de novo expression of Cu, Zn superoxide dismutase, up-regulated allergen Asp f3 expression and down-regulated catalase and a peroxiredoxin levels. Significantly elevated glutathione GSH levels (p < 0.05), along with concomitant resistance to diamide, were evident in A. fumigatus DgliT, lacking gliotoxin oxidoreductase, a gliotoxin self-protection gene. Saccharomyces cerevisiae deletents (Dsod1 and Dyap1) were hypersensitive to exogenous gliotoxin, while Dgsh1 was resistant. Significant gliotoxin-mediated (5 lg/ml) growth inhibition (p < 0.001) of Aspergillus nidulans, Aspergillus terreus, Aspergillus niger, Cochliobolus heterostrophus and Neurospora crassa was also observed. Growth of Aspergillus flavus, Fusarium graminearum and Aspergillus oryzae was significantly inhibited (p < 0.001) at gliotoxin (10 lg/ml), indicating differential gliotoxin sensitivity amongst fungi. Re-introduction of gliT into A. fumigatus DgliT, at a different locus (ctsD; AFUA_4G07040, an aspartic protease), with selection on gliotoxin, facilitated deletion of ctsD without use of additional antibiotic selection markers. Absence of ctsD expression was accompanied by restoration of gliT expression, and resistance to gliotoxin. Thus, we propose gliT/gliotoxin as a useful selection marker system for fungal transformation. Finally, we suggest incorporation of gliotoxin sensitivity assays into all future fungal functional genomic studies.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Gliotoxin effects on fungal growth: Mechanisms and exploitation

Carberry

Molloy

Hammel

et al. 2012

Fungal Genetics and Biology

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“…In an attempt to gain insight into the in vivo effects of gliotoxin exposure, Chamilos and colleagues [60] screened a yeast deletion library to identify strains that were sensitive or resistant to exogenous gliotoxin compared to wild type. While a number of gene deletions caused changes in the gliotoxin exposure profile, of particular note was the finding that deletion of cys3, which encodes a cystathionine g-lyase, caused sensitization to gliotoxin.…”

Section: Gliotoxin Functionality In Fungimentioning

confidence: 99%

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

Dolan¹,

O’Keeffe²,

Jones

et al. 2015

Trends in Microbiology

146

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Gliotoxin biosynthesis is encoded by the gli gene cluster in Aspergillus fumigatus. The biosynthesis of gliotoxin is influenced by a suite of transcriptionally-active regulatory proteins and a bis-thiomethyltransferase. A selfprotection system against gliotoxin is present in A. fumigatus. Several additional metabolites are also produced via the gliotoxin biosynthetic pathway. Moreover, the biosynthesis of unrelated natural products appears to be influenced either by gliotoxin or by the activity of specific reactions within the biosynthetic pathway. The activity of gliotoxin against animal cells and fungi, often mediated by interference with redox homeostasis or protein modification, is revealing new metabolic interactions within eukaryotic systems. Nature has provided a most useful natural product with which to reveal some of its many molecular secrets. Contextualizing and rethinking gliotoxinAspergillus fumigatus is an opportunistic fungal pathogen and primarily infects immunocompromised individuals where it can cause fatal invasive aspergillosis (IA) [1]. A. fumigatus exposure can also induce debilitating aspergillosis and allergy in immunocompetent individuals [2,3]. Selected secondary metabolites produced by A. fumigatus, in particular siderophores and the non-ribosomal peptide gliotoxin, are generally considered to be front-line virulence factors [4,5]. Gliotoxin is an epipolythiodioxopiperazine (ETP) of molecular mass 326 Da, and contains a disulfide bridge which can undergo repeating cleavage and reformation, thereby resulting in a potent intracellular redox activity (Figure 1) [6]. Indeed, the dithiol form of gliotoxin has also been posited to be responsible for the observed biological activities of gliotoxin [7]. Bisdethiobis(methylthio)gliotoxin (BmGT) and related gliotoxin metabolites (Figure 1) are also biosynthesized by A. fumigatus [8,9]. Incredibly, the gliotoxin biosynthetic pathway had remained elusive since the discovery of gliotoxin in 1936; however, recent studies have not only dissected this unusual molecular assembly system but have revealed the necessity for gliotoxin-producing fungi to possess an endogenous resistance system against gliotoxin [10,11]. Moreover, because gliotoxin can be considered as the prototype ETP, studies on gliotoxin can be instrumental in revealing the biosynthetic mechanisms of related ETPs which are biosynthesized by a range of fungi [12]. Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].In addition to studying how gliotoxin contributes to organismal virulence, it has also been deployed to explore and reveal novel biochemistry within both fungal and animal cells [15,16]. Thus, we contend that it is the ability of gliotoxin to interfere with so many cellular processes that makes it...

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“…that has been extensively studied because of its cytotoxic and immunosuppressive effects on mammalian cells [1,2]. Model eukaryotic fungal organisms (e.g., Saccharomyces cerevisiae) have been used to screen genes associated with GT resistance or sensitivity as a model system for the impact of GT on animal cells [3], however, little is known about the effect that this toxin has on other fungi. The production of GT within the Aspergillus genus is inconsistent, for example, pathogenic fungi like A. fumigatus can produce GT while A. niger and Aspergillus nidulans lack the gli cluster responsible for the biosynthesis of the toxin [4].…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger

Manzanares-Miralles

Sarikaya-Bayram

Smith

et al. 2016

Journal of Proteomics

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a b s t r a c t a r t i c l e i n f oGliotoxin (GT) is a redox-active metabolite, produced by Aspergillus fumigatus, which inhibits the growth of other fungi. Here we demonstrate how Aspergillus niger responds to GT exposure. Quantitative proteomics revealed that GT dysregulated the abundance of 378 proteins including those involved in methionine metabolism and induced de novo abundance of two S-adenosylmethionine (SAM)-dependent methyltransferases. Increased abundance of enzymes S-adenosylhomocysteinase (p = 0.0018) required for homocysteine generation from S-adenosylhomocysteine (SAH), and spermidine synthase (p = 0.0068), involved in the recycling of Met, was observed. Analysis of Met-related metabolites revealed significant increases in the levels of Met and adenosine, in correlation with proteomic data. Methyltransferase MT-II is responsible for bisthiobis(methylthio)gliotoxin (BmGT) formation, deletion of MT-II abolished BmGT formation and led to increased GT sensitivity in A. niger. Proteomic analysis also revealed that GT exposure also significantly (p b 0.05) increased hydrolytic enzyme abundance, including glycoside hydrolases (n = 22) and peptidases (n = 16). We reveal that in an attempt to protect against the detrimental affects of GT, methyltransferase-mediated GT thiomethylation alters cellular pathways involving Met and SAM, with consequential dysregulation of hydrolytic enzyme abundance in A. niger. Thus, it provides new opportunities to exploit the response of GT-naïve fungi to GT.

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Genomewide Screening for Genes Associated with Gliotoxin Resistance and Sensitivity in Saccharomyces cerevisiae

Cited by 13 publications

References 26 publications

Gliotoxin effects on fungal growth: Mechanisms and exploitation

Gliotoxin effects on fungal growth: Mechanisms and exploitation

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger

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