Limits...
Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus.

Amich J, Schafferer L, Haas H, Krappmann S - PLoS Pathog. (2013)

Bottom Line: Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent.The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus.Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Infectious Diseases, Julius-Maximilians-University Würzburg, Würzburg, Germany.

ABSTRACT
Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

Show MeSH

Related in: MedlinePlus

Schematic overview on the impact of MetR regulation on sulphur metabolism.The MetR regulon (gray genes and arrows) comprises genes whose products participate in sulphur assimilation, especially inorganic sulphur, rather than metabolic processes (black arrows). Full-line arrows denote known genes/pathways while dashed arrows denote putative pathways. The supposed point of connection with iron sensing/regulation is highlighted.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3757043&req=5

ppat-1003573-g009: Schematic overview on the impact of MetR regulation on sulphur metabolism.The MetR regulon (gray genes and arrows) comprises genes whose products participate in sulphur assimilation, especially inorganic sulphur, rather than metabolic processes (black arrows). Full-line arrows denote known genes/pathways while dashed arrows denote putative pathways. The supposed point of connection with iron sensing/regulation is highlighted.

Mentions: The information gathered in this work suggests that the MetR regulon directly affects genes whose products are related to assimilation processes of sulphur (especially inorganic sulphur), rather than metabolic processes (Fig. 9). Presence of the MetR transcription factor is essential for growth on several sulphur sources, specifically on those containing inorganic sulphur sources. Accordingly, MetR is required for activation of transcription of genes encoding enzymes of the sulphate assimilation pathway and an arylsulphatase activity, which demonstrates a direct role of MetR in inorganic sulphur acquisition. Remarkably, the metRΔ mutant was able to use cysteine and the Glu-Cys-Gly tripeptide glutathione as a source of sulphur only under nitrogen-starving conditions, implicating a link between S- and N-acquisition. One possible explanation is that under nitrogen-limiting conditions increased expression of amino acid permeases and oligopeptide transporters facilitates uptake of these particular sulphur-containing compounds, which then can be exploited as S-source. Since no specific enzymes for cysteine catabolism have been identified so far, this scenario could not be investigated further. The fact that the expression of the methionine aminotransferase-encoding gene metAT is elevated in the presence of cysteine suggests that this amino acid might be transformed into methionine rather than being catabolized directly. Accordingly, catabolism of cysteine as sulphur source appears to be MetR-independent and, therefore, its uptake might represent a bottle neck that prevents the mutant to utilize cysteine. This notion is further supported by the fact that in the RNA-seq data set expression of the oligopeptide transporter OptG (AFUA_6G03140), the orthologue to the C. albicans glutathione transporter OPT7[23], was observed to be expressed higher in the wild-type than in the metRΔ mutant. Thus, cynA and optG are candidate genes to support A. fumigatus growth in the presence of cysteine and glutathione, but further studies are needed to elucidate whether they encode specific A. fumigatus transporters and whether cysteine acid is catabolized directly.


Regulation of sulphur assimilation is essential for virulence and affects iron homeostasis of the human-pathogenic mould Aspergillus fumigatus.

Amich J, Schafferer L, Haas H, Krappmann S - PLoS Pathog. (2013)

Schematic overview on the impact of MetR regulation on sulphur metabolism.The MetR regulon (gray genes and arrows) comprises genes whose products participate in sulphur assimilation, especially inorganic sulphur, rather than metabolic processes (black arrows). Full-line arrows denote known genes/pathways while dashed arrows denote putative pathways. The supposed point of connection with iron sensing/regulation is highlighted.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757043&req=5

ppat-1003573-g009: Schematic overview on the impact of MetR regulation on sulphur metabolism.The MetR regulon (gray genes and arrows) comprises genes whose products participate in sulphur assimilation, especially inorganic sulphur, rather than metabolic processes (black arrows). Full-line arrows denote known genes/pathways while dashed arrows denote putative pathways. The supposed point of connection with iron sensing/regulation is highlighted.
Mentions: The information gathered in this work suggests that the MetR regulon directly affects genes whose products are related to assimilation processes of sulphur (especially inorganic sulphur), rather than metabolic processes (Fig. 9). Presence of the MetR transcription factor is essential for growth on several sulphur sources, specifically on those containing inorganic sulphur sources. Accordingly, MetR is required for activation of transcription of genes encoding enzymes of the sulphate assimilation pathway and an arylsulphatase activity, which demonstrates a direct role of MetR in inorganic sulphur acquisition. Remarkably, the metRΔ mutant was able to use cysteine and the Glu-Cys-Gly tripeptide glutathione as a source of sulphur only under nitrogen-starving conditions, implicating a link between S- and N-acquisition. One possible explanation is that under nitrogen-limiting conditions increased expression of amino acid permeases and oligopeptide transporters facilitates uptake of these particular sulphur-containing compounds, which then can be exploited as S-source. Since no specific enzymes for cysteine catabolism have been identified so far, this scenario could not be investigated further. The fact that the expression of the methionine aminotransferase-encoding gene metAT is elevated in the presence of cysteine suggests that this amino acid might be transformed into methionine rather than being catabolized directly. Accordingly, catabolism of cysteine as sulphur source appears to be MetR-independent and, therefore, its uptake might represent a bottle neck that prevents the mutant to utilize cysteine. This notion is further supported by the fact that in the RNA-seq data set expression of the oligopeptide transporter OptG (AFUA_6G03140), the orthologue to the C. albicans glutathione transporter OPT7[23], was observed to be expressed higher in the wild-type than in the metRΔ mutant. Thus, cynA and optG are candidate genes to support A. fumigatus growth in the presence of cysteine and glutathione, but further studies are needed to elucidate whether they encode specific A. fumigatus transporters and whether cysteine acid is catabolized directly.

Bottom Line: Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent.The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus.Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Infectious Diseases, Julius-Maximilians-University Würzburg, Würzburg, Germany.

ABSTRACT
Sulphur is an essential element that all pathogens have to absorb from their surroundings in order to grow inside their infected host. Despite its importance, the relevance of sulphur assimilation in fungal virulence is largely unexplored. Here we report a role of the bZIP transcription factor MetR in sulphur assimilation and virulence of the human pathogen Aspergillus fumigatus. The MetR regulator is essential for growth on a variety of sulphur sources; remarkably, it is fundamental for assimilation of inorganic S-sources but dispensable for utilization of methionine. Accordingly, it strongly supports expression of genes directly related to inorganic sulphur assimilation but not of genes connected to methionine metabolism. On a broader scale, MetR orchestrates the comprehensive transcriptional adaptation to sulphur-starving conditions as demonstrated by digital gene expression analysis. Surprisingly, A. fumigatus is able to utilize volatile sulphur compounds produced by its methionine catabolism, a process that has not been described before and that is MetR-dependent. The A. fumigatus MetR transcriptional activator is important for virulence in both leukopenic mice and an alternative mini-host model of aspergillosis, as it was essential for the development of pulmonary aspergillosis and supported the systemic dissemination of the fungus. MetR action under sulphur-starving conditions is further required for proper iron regulation, which links regulation of sulphur metabolism to iron homeostasis and demonstrates an unprecedented regulatory crosstalk. Taken together, this study provides evidence that regulation of sulphur assimilation is not only crucial for A. fumigatus virulence but also affects the balance of iron in this prime opportunistic pathogen.

Show MeSH
Related in: MedlinePlus