The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism
ABSTRACTSphingofungins are sphinganine analog mycotoxins acting as inhibitors of serine palmitoyl transferases, enzymes responsible for the first step in the sphingolipid biosynthesis. Eukaryotic cells are highly organized with various structures and organelles to facilitate cellular processes and c...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2024-03-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00195-24 |
| _version_ | 1797263238057951232 |
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| author | Katarina Jojić Fabio Gherlone Zoltán Cseresnyés Alexander U. Bissell Sandra Hoefgen Stefan Hoffmann Ying Huang Slavica Janevska Marc Thilo Figge Vito Valiante |
| author_facet | Katarina Jojić Fabio Gherlone Zoltán Cseresnyés Alexander U. Bissell Sandra Hoefgen Stefan Hoffmann Ying Huang Slavica Janevska Marc Thilo Figge Vito Valiante |
| author_sort | Katarina Jojić |
| collection | DOAJ |
| description | ABSTRACTSphingofungins are sphinganine analog mycotoxins acting as inhibitors of serine palmitoyl transferases, enzymes responsible for the first step in the sphingolipid biosynthesis. Eukaryotic cells are highly organized with various structures and organelles to facilitate cellular processes and chemical reactions, including the ones occurring as part of the secondary metabolism. We studied how sphingofungin biosynthesis is compartmentalized in the human-pathogenic fungus Aspergillus fumigatus, and we observed that it takes place in the endoplasmic reticulum (ER), ER-derived vesicles, and the cytosol. This implies that sphingofungin and sphingolipid biosynthesis colocalize to some extent. Automated analysis of confocal microscopy images confirmed the colocalization of the fluorescent proteins. Moreover, we demonstrated that the cluster-associated aminotransferase (SphA) and 3-ketoreductase (SphF) play a bifunctional role, supporting sphingolipid biosynthesis, and thereby antagonizing the toxic effects caused by sphingofungin production.IMPORTANCEA balanced sphingolipid homeostasis is critical for the proper functioning of eukaryotic cells. To this end, sphingolipid inhibitors have therapeutic potential against diseases related to the deregulation of sphingolipid balance. In addition, some of them have significant antifungal activity, suggesting that sphingolipid inhibitors-producing fungi have evolved mechanisms to escape self-poisoning. Here, we propose a novel self-defense mechanism, with cluster-associated genes coding for enzymes that play a dual role, being involved in both sphingofungin and sphingolipid production. |
| first_indexed | 2024-04-25T00:09:49Z |
| format | Article |
| id | doaj.art-1590b18aa1de4795b6dcabe17f244522 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-25T00:09:49Z |
| publishDate | 2024-03-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-1590b18aa1de4795b6dcabe17f2445222024-03-13T14:01:04ZengAmerican Society for MicrobiologymBio2150-75112024-03-0115310.1128/mbio.00195-24The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolismKatarina Jojić0Fabio Gherlone1Zoltán Cseresnyés2Alexander U. Bissell3Sandra Hoefgen4Stefan Hoffmann5Ying Huang6Slavica Janevska7Marc Thilo Figge8Vito Valiante9Biobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyBiobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyApplied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyBiobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyBiobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyFaculty of Biological Sciences, Friedrich Schiller University Jena, Jena, GermanyBiobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany(Epi-)Genetic Regulation of Fungal Virulence, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyFaculty of Biological Sciences, Friedrich Schiller University Jena, Jena, GermanyBiobricks of Microbial Natural Product Syntheses, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, GermanyABSTRACTSphingofungins are sphinganine analog mycotoxins acting as inhibitors of serine palmitoyl transferases, enzymes responsible for the first step in the sphingolipid biosynthesis. Eukaryotic cells are highly organized with various structures and organelles to facilitate cellular processes and chemical reactions, including the ones occurring as part of the secondary metabolism. We studied how sphingofungin biosynthesis is compartmentalized in the human-pathogenic fungus Aspergillus fumigatus, and we observed that it takes place in the endoplasmic reticulum (ER), ER-derived vesicles, and the cytosol. This implies that sphingofungin and sphingolipid biosynthesis colocalize to some extent. Automated analysis of confocal microscopy images confirmed the colocalization of the fluorescent proteins. Moreover, we demonstrated that the cluster-associated aminotransferase (SphA) and 3-ketoreductase (SphF) play a bifunctional role, supporting sphingolipid biosynthesis, and thereby antagonizing the toxic effects caused by sphingofungin production.IMPORTANCEA balanced sphingolipid homeostasis is critical for the proper functioning of eukaryotic cells. To this end, sphingolipid inhibitors have therapeutic potential against diseases related to the deregulation of sphingolipid balance. In addition, some of them have significant antifungal activity, suggesting that sphingolipid inhibitors-producing fungi have evolved mechanisms to escape self-poisoning. Here, we propose a novel self-defense mechanism, with cluster-associated genes coding for enzymes that play a dual role, being involved in both sphingofungin and sphingolipid production.https://journals.asm.org/doi/10.1128/mbio.00195-24sphingofunginssphingolipidAspergillus fumigatussecondary metabolitescellular compartments |
| spellingShingle | Katarina Jojić Fabio Gherlone Zoltán Cseresnyés Alexander U. Bissell Sandra Hoefgen Stefan Hoffmann Ying Huang Slavica Janevska Marc Thilo Figge Vito Valiante The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism mBio sphingofungins sphingolipid Aspergillus fumigatus secondary metabolites cellular compartments |
| title | The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism |
| title_full | The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism |
| title_fullStr | The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism |
| title_full_unstemmed | The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism |
| title_short | The spatial organization of sphingofungin biosynthesis in Aspergillus fumigatus and its cross-interaction with sphingolipid metabolism |
| title_sort | spatial organization of sphingofungin biosynthesis in aspergillus fumigatus and its cross interaction with sphingolipid metabolism |
| topic | sphingofungins sphingolipid Aspergillus fumigatus secondary metabolites cellular compartments |
| url | https://journals.asm.org/doi/10.1128/mbio.00195-24 |
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