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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.

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Related in: MedlinePlus

MetR of Aspergillus fumigatus is highly conserved and translocates to the nucleus upon sulphur starvation.(A) Alignment of Aspergillus fumigatus (Af) and A. nidulans (An) MetR proteins. Identical residues are shadowed in black and similar residues in grey. The bZIP region is framed in the black rectangle. (B) Exemplary molecular phylogenetic tree of the amino acid sequences of MetR/CYS-3 proteins of several ascomycota species. Multiple alignment and phylogenetic tree were created using CLC Sequence Viewer software (Workbench). Protein accession numbers are as follows: Ajellomyces dermatitidis EEQ78187, A. fumigatus EAL90135.1, Arthroderma gypseum EFQ98814, A. nidulans AF148535_1, Coccidioides posadasii EER26081, Gibberella zeae EAA74455.1, Magnaporthe oryzae EHA57141; Neurospora crassa AAA33585, Neosartorya fischeri EAW25471.1, Paracoccidioides brasiliensis EEH48461, Penicillium marneffei EEA27939, Pyrenophora tritici-repentis EDU47197. (C) Localisation of a functional MetR-GFP derivative in the presence or absence of sulphate as sole source of sulphur. Within 90 minutes of S-starvation, cytoplasmic localisation of the regulator changes to nuclear as demonstrated by co-localisation of the fluorescent signal with the nuclear stain DAPI.
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ppat-1003573-g001: MetR of Aspergillus fumigatus is highly conserved and translocates to the nucleus upon sulphur starvation.(A) Alignment of Aspergillus fumigatus (Af) and A. nidulans (An) MetR proteins. Identical residues are shadowed in black and similar residues in grey. The bZIP region is framed in the black rectangle. (B) Exemplary molecular phylogenetic tree of the amino acid sequences of MetR/CYS-3 proteins of several ascomycota species. Multiple alignment and phylogenetic tree were created using CLC Sequence Viewer software (Workbench). Protein accession numbers are as follows: Ajellomyces dermatitidis EEQ78187, A. fumigatus EAL90135.1, Arthroderma gypseum EFQ98814, A. nidulans AF148535_1, Coccidioides posadasii EER26081, Gibberella zeae EAA74455.1, Magnaporthe oryzae EHA57141; Neurospora crassa AAA33585, Neosartorya fischeri EAW25471.1, Paracoccidioides brasiliensis EEH48461, Penicillium marneffei EEA27939, Pyrenophora tritici-repentis EDU47197. (C) Localisation of a functional MetR-GFP derivative in the presence or absence of sulphate as sole source of sulphur. Within 90 minutes of S-starvation, cytoplasmic localisation of the regulator changes to nuclear as demonstrated by co-localisation of the fluorescent signal with the nuclear stain DAPI.

Mentions: The A. fumigatus MetR transcription factor was identified by BLAST search [42], [43], [44] on the NCBI server (http://www.ncbi.nlm.nih.gov/) using the A. nidulans MetR protein sequence (PubMed acc. no. AAD38380) as a query, revealing 64% identity and 75% similarity between both proteins (Fig. 1A). Notably, the leucine zipper (bZIP) domains of the factors are virtually identical with 97% identity and 100% similarity, which suggests that both could recognize a similar DNA target sequence.


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)

MetR of Aspergillus fumigatus is highly conserved and translocates to the nucleus upon sulphur starvation.(A) Alignment of Aspergillus fumigatus (Af) and A. nidulans (An) MetR proteins. Identical residues are shadowed in black and similar residues in grey. The bZIP region is framed in the black rectangle. (B) Exemplary molecular phylogenetic tree of the amino acid sequences of MetR/CYS-3 proteins of several ascomycota species. Multiple alignment and phylogenetic tree were created using CLC Sequence Viewer software (Workbench). Protein accession numbers are as follows: Ajellomyces dermatitidis EEQ78187, A. fumigatus EAL90135.1, Arthroderma gypseum EFQ98814, A. nidulans AF148535_1, Coccidioides posadasii EER26081, Gibberella zeae EAA74455.1, Magnaporthe oryzae EHA57141; Neurospora crassa AAA33585, Neosartorya fischeri EAW25471.1, Paracoccidioides brasiliensis EEH48461, Penicillium marneffei EEA27939, Pyrenophora tritici-repentis EDU47197. (C) Localisation of a functional MetR-GFP derivative in the presence or absence of sulphate as sole source of sulphur. Within 90 minutes of S-starvation, cytoplasmic localisation of the regulator changes to nuclear as demonstrated by co-localisation of the fluorescent signal with the nuclear stain DAPI.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1003573-g001: MetR of Aspergillus fumigatus is highly conserved and translocates to the nucleus upon sulphur starvation.(A) Alignment of Aspergillus fumigatus (Af) and A. nidulans (An) MetR proteins. Identical residues are shadowed in black and similar residues in grey. The bZIP region is framed in the black rectangle. (B) Exemplary molecular phylogenetic tree of the amino acid sequences of MetR/CYS-3 proteins of several ascomycota species. Multiple alignment and phylogenetic tree were created using CLC Sequence Viewer software (Workbench). Protein accession numbers are as follows: Ajellomyces dermatitidis EEQ78187, A. fumigatus EAL90135.1, Arthroderma gypseum EFQ98814, A. nidulans AF148535_1, Coccidioides posadasii EER26081, Gibberella zeae EAA74455.1, Magnaporthe oryzae EHA57141; Neurospora crassa AAA33585, Neosartorya fischeri EAW25471.1, Paracoccidioides brasiliensis EEH48461, Penicillium marneffei EEA27939, Pyrenophora tritici-repentis EDU47197. (C) Localisation of a functional MetR-GFP derivative in the presence or absence of sulphate as sole source of sulphur. Within 90 minutes of S-starvation, cytoplasmic localisation of the regulator changes to nuclear as demonstrated by co-localisation of the fluorescent signal with the nuclear stain DAPI.
Mentions: The A. fumigatus MetR transcription factor was identified by BLAST search [42], [43], [44] on the NCBI server (http://www.ncbi.nlm.nih.gov/) using the A. nidulans MetR protein sequence (PubMed acc. no. AAD38380) as a query, revealing 64% identity and 75% similarity between both proteins (Fig. 1A). Notably, the leucine zipper (bZIP) domains of the factors are virtually identical with 97% identity and 100% similarity, which suggests that both could recognize a similar DNA target sequence.

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