The
            <i>mtfA</i>
            Transcription Factor Gene Controls Morphogenesis, Gliotoxin Production, and Virulence in the Opportunistic Human Pathogen Aspergillus fumigatus

Smith, Timothy D.; Calvo, Ana M.

doi:10.1128/ec.00075-14

Cited by 23 publications

(38 citation statements)

References 66 publications

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“…We next examined the role of the recently identified SM regulator MtfA [ 29 , 30 ] in A . fumigatus and A .…”

Section: Resultsmentioning

confidence: 99%

“…nidulans by performing RNA sequencing and differential gene expression analysis of Δ mtfA vs WT strains of both species ( A . fumigatus tTDS4.1 Δ mtfA [ 30 ] and CEA10, A . nidulans TRVp Δ mtfA and TRV50.2 [ 29 ]).…”

Section: Resultsmentioning

confidence: 99%

“…nidulans , but not in A . fumigatus [ 28 – 30 ], as its expression is decreased in Δ veA vs WT in A . nidulans but not in Δ veA vs WT in A .…”

Section: Discussionmentioning

confidence: 99%

“…nidulans ; in A . fumigatus , MtfA is necessary for normal protease activity, and virulence assays using the moth Galleria mellonella suggest it plays a role in pathogenicity [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Examining the Evolution of the Regulatory Circuit Controlling Secondary Metabolism and Development in the Fungal Genus Aspergillus

et al. 2015

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Filamentous fungi produce diverse secondary metabolites (SMs) essential to their ecology and adaptation. Although each SM is typically produced by only a handful of species, global SM production is governed by widely conserved transcriptional regulators in conjunction with other cellular processes, such as development. We examined the interplay between the taxonomic narrowness of SM distribution and the broad conservation of global regulation of SM and development in Aspergillus, a diverse fungal genus whose members produce well-known SMs such as penicillin and gliotoxin. Evolutionary analysis of the 2,124 genes comprising the 262 SM pathways in four Aspergillus species showed that most SM pathways were species-specific, that the number of SM gene orthologs was significantly lower than that of orthologs in primary metabolism, and that the few conserved SM orthologs typically belonged to non-homologous SM pathways. RNA sequencing of two master transcriptional regulators of SM and development, veA and mtfA, showed that the effects of deletion of each gene, especially veA, on SM pathway regulation were similar in A. fumigatus and A. nidulans, even though the underlying genes and pathways regulated in each species differed. In contrast, examination of the role of these two regulators in development, where 94% of the underlying genes are conserved in both species showed that whereas the role of veA is conserved, mtfA regulates development in the homothallic A. nidulans but not in the heterothallic A. fumigatus. Thus, the regulation of these highly conserved developmental genes is divergent, whereas–despite minimal conservation of target genes and pathways–the global regulation of SM production is largely conserved. We suggest that the evolution of the transcriptional regulation of secondary metabolism in Aspergillus represents a novel type of regulatory circuit rewiring and hypothesize that it has been largely driven by the dramatic turnover of the target genes involved in the process.

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“…We next examined the role of the recently identified SM regulator MtfA [ 29 , 30 ] in A . fumigatus and A .…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…nidulans , but not in A . fumigatus [ 28 – 30 ], as its expression is decreased in Δ veA vs WT in A . nidulans but not in Δ veA vs WT in A .…”

Section: Discussionmentioning

confidence: 99%

“…nidulans ; in A . fumigatus , MtfA is necessary for normal protease activity, and virulence assays using the moth Galleria mellonella suggest it plays a role in pathogenicity [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Examining the Evolution of the Regulatory Circuit Controlling Secondary Metabolism and Development in the Fungal Genus Aspergillus

et al. 2015

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“…In addition, it is wellestablished that laeA, a global regulator of secondary metabolism, which interacts with the velvet proteins VeA and VelB in the nucleus [32][33][34][35], augments gliotoxin biosynthesis because either laeA or veA deletion results in impaired gliotoxin production in A. fumigatus [34,36]. Other transcription factors found to regulate the gli cluster include mtfA (a C 2 H 2 transcription factor [37]), rsmA (a bZIP transcription factor [38]), and stuA (an APSES family transcription factor [39,40] Figure 1. Interconversion of gliotoxin between the reduced (dithiol) and oxidized (disulfide) forms.…”

Section: Gliotoxin Biosynthesismentioning

confidence: 99%

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

Dolan¹,

O’Keeffe²,

Jones

et al. 2015

Trends in Microbiology

102

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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