The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus
In contrast to mammalia, fungi are able to synthesize the branched-chain amino acid leucine de novo. Recently, the transcription factor LeuB has been shown to cross-regulate leucine biosynthesis, nitrogen metabolism and iron homeostasis in Aspergillus fumigatus, the most common human mold pathogen....
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Virulence |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21505594.2019.1682760 |
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| author | Thomas Orasch Anna-Maria Dietl Yana Shadkchan Ulrike Binder Ingo Bauer Cornelia Lass-Flörl Nir Osherov Hubertus Haas |
| author_facet | Thomas Orasch Anna-Maria Dietl Yana Shadkchan Ulrike Binder Ingo Bauer Cornelia Lass-Flörl Nir Osherov Hubertus Haas |
| author_sort | Thomas Orasch |
| collection | DOAJ |
| description | In contrast to mammalia, fungi are able to synthesize the branched-chain amino acid leucine de novo. Recently, the transcription factor LeuB has been shown to cross-regulate leucine biosynthesis, nitrogen metabolism and iron homeostasis in Aspergillus fumigatus, the most common human mold pathogen. Moreover, the leucine biosynthetic pathway intermediate α-isopropylmalate (α-IPM) has previously been shown to posttranslationally activate LeuB homologs in S. cerevisiae and A. nidulans. Here, we demonstrate that in A. fumigatus inactivation of both leucine biosynthetic enzymes α-IPM synthase (LeuC), which disrupts α-IPM synthesis, and α-IPM isomerase (LeuA), which causes cellular α-IPM accumulation, results in leucine auxotrophy. However, compared to lack of LeuA, lack of LeuC resulted in increased leucine dependence, a growth defect during iron starvation and decreased expression of LeuB-regulated genes including genes involved in iron acquisition. Lack of either LeuA or LeuC decreased virulence in an insect infection model, and inactivation of LeuC rendered A. fumigatus avirulent in a pulmonary aspergillosis mouse model. Taken together, we demonstrate that the lack of two leucine biosynthetic enzymes, LeuA and LeuC, results in significant phenotypic consequences indicating that the regulator LeuB is activated by α-IPM in A. fumigatus and that the leucine biosynthetic pathway is an attractive target for the development of antifungal drugs. |
| first_indexed | 2024-12-10T08:17:28Z |
| format | Article |
| id | doaj.art-dae059ba5a384f48b7621b5c1330a22d |
| institution | Directory Open Access Journal |
| issn | 2150-5594 2150-5608 |
| language | English |
| last_indexed | 2024-12-10T08:17:28Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Virulence |
| spelling | doaj.art-dae059ba5a384f48b7621b5c1330a22d2022-12-22T01:56:26ZengTaylor & Francis GroupVirulence2150-55942150-56082019-01-0110192593410.1080/21505594.2019.16827601682760The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatusThomas Orasch0Anna-Maria Dietl1Yana Shadkchan2Ulrike Binder3Ingo Bauer4Cornelia Lass-Flörl5Nir Osherov6Hubertus Haas7Medical University of InnsbruckMedical University of InnsbruckSackler School of Medicine, Tel Aviv UniversityMedical University of InnsbruckMedical University of InnsbruckMedical University of InnsbruckSackler School of Medicine, Tel Aviv UniversityMedical University of InnsbruckIn contrast to mammalia, fungi are able to synthesize the branched-chain amino acid leucine de novo. Recently, the transcription factor LeuB has been shown to cross-regulate leucine biosynthesis, nitrogen metabolism and iron homeostasis in Aspergillus fumigatus, the most common human mold pathogen. Moreover, the leucine biosynthetic pathway intermediate α-isopropylmalate (α-IPM) has previously been shown to posttranslationally activate LeuB homologs in S. cerevisiae and A. nidulans. Here, we demonstrate that in A. fumigatus inactivation of both leucine biosynthetic enzymes α-IPM synthase (LeuC), which disrupts α-IPM synthesis, and α-IPM isomerase (LeuA), which causes cellular α-IPM accumulation, results in leucine auxotrophy. However, compared to lack of LeuA, lack of LeuC resulted in increased leucine dependence, a growth defect during iron starvation and decreased expression of LeuB-regulated genes including genes involved in iron acquisition. Lack of either LeuA or LeuC decreased virulence in an insect infection model, and inactivation of LeuC rendered A. fumigatus avirulent in a pulmonary aspergillosis mouse model. Taken together, we demonstrate that the lack of two leucine biosynthetic enzymes, LeuA and LeuC, results in significant phenotypic consequences indicating that the regulator LeuB is activated by α-IPM in A. fumigatus and that the leucine biosynthetic pathway is an attractive target for the development of antifungal drugs.http://dx.doi.org/10.1080/21505594.2019.1682760aspergillus fumigatusleucinevirulenceironamino acid biosynthesis |
| spellingShingle | Thomas Orasch Anna-Maria Dietl Yana Shadkchan Ulrike Binder Ingo Bauer Cornelia Lass-Flörl Nir Osherov Hubertus Haas The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus Virulence aspergillus fumigatus leucine virulence iron amino acid biosynthesis |
| title | The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus |
| title_full | The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus |
| title_fullStr | The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus |
| title_full_unstemmed | The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus |
| title_short | The leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in Aspergillus fumigatus |
| title_sort | leucine biosynthetic pathway is crucial for adaptation to iron starvation and virulence in aspergillus fumigatus |
| topic | aspergillus fumigatus leucine virulence iron amino acid biosynthesis |
| url | http://dx.doi.org/10.1080/21505594.2019.1682760 |
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