SCF Ubiquitin Ligase F-box Protein Fbx15 Controls Nuclear Co-repressor Localization, Stress Response and Virulence of the Human Pathogen Aspergillus fumigatus
| Autor: | Anja Abelmann, Derek J. Mattern, Oliver Valerius, Thorsten Heinekamp, Axel A. Brakhage, Bastian Jöhnk, Gerhard H. Braus, Özgür Bayram, Ilse D. Jacobsen |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Aspergillus Nidulans Cytoplasm Physiology Complement System Yeast and Fungal Models Pathology and Laboratory Medicine F-box protein Biochemistry Aspergillus fumigatus chemistry.chemical_compound Mice Ubiquitin Immune Physiology Gene Expression Regulation Fungal Medicine and Health Sciences Biology (General) Post-Translational Modification Phosphorylation lcsh:QH301-705.5 Derepression Fungal Pathogens Immune System Proteins biology Gliotoxin Virulence Animal Models Cullin Proteins Cell biology Protein Transport Aspergillus Aspergillus Fumigatus Medical Microbiology CUL1 Female Pathogens Cellular Structures and Organelles Co-Repressor Proteins Research Article lcsh:Immunologic diseases. Allergy QH301-705.5 Virulence Factors 030106 microbiology Immunology Mouse Models Mycology Research and Analysis Methods Microbiology Fungal Proteins 03 medical and health sciences Model Organisms Virology Skp1 Genetics Animals Aspergillosis Humans Amino Acid Sequence Molecular Biology Microbial Pathogens Ubiquitins SKP Cullin F-Box Protein Ligases F-Box Proteins Organisms Fungi Biology and Life Sciences Proteins Oxidative stress Aspergillus nidulans Mouse models Virulence factors Complement system Cell Biology RC581-607 biology.organism_classification Molds (Fungi) Oxidative Stress Disease Models Animal 030104 developmental biology lcsh:Biology (General) chemistry Immune System Mutation biology.protein Parasitology Immunologic diseases. Allergy lcsh:RC581-607 Nuclear localization sequence |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 12, Iss 9, p e1005899 (2016) |
| Popis: | F-box proteins share the F-box domain to connect substrates of E3 SCF ubiquitin RING ligases through the adaptor Skp1/A to Cul1/A scaffolds. F-box protein Fbx15 is part of the general stress response of the human pathogenic mold Aspergillus fumigatus. Oxidative stress induces a transient peak of fbx15 expression, resulting in 3x elevated Fbx15 protein levels. During non-stress conditions Fbx15 is phosphorylated and F-box mediated interaction with SkpA preferentially happens in smaller subpopulations in the cytoplasm. The F-box of Fbx15 is required for an appropriate oxidative stress response, which results in rapid dephosphorylation of Fbx15 and a shift of the cellular interaction with SkpA to the nucleus. Fbx15 binds SsnF/Ssn6 as part of the RcoA/Tup1-SsnF/Ssn6 co-repressor and is required for its correct nuclear localization. Dephosphorylated Fbx15 prevents SsnF/Ssn6 nuclear localization and results in the derepression of gliotoxin gene expression. fbx15 deletion mutants are unable to infect immunocompromised mice in a model for invasive aspergillosis. Fbx15 has a novel dual molecular function by controlling transcriptional repression and being part of SCF E3 ubiquitin ligases, which is essential for stress response, gliotoxin production and virulence in the opportunistic human pathogen A. fumigatus. Author Summary The opportunistic human fungal pathogen Aspergillus fumigatus is the most prevalent cause for severe fungal infections in immunocompromised hosts. A major virulence factor of A. fumigatus is its ability to rapidly adapt to host conditions during infection. The rapid response to environmental changes underlies a well-balanced system of production and degradation of proteins. The degradation of specific target proteins is mediated by ubiquitin-protein ligases (E3), which mark their target proteins with ubiquitin for proteasomal degradation. Multisubunit SCF Cullin1 Ring ligases (CRL) are E3 ligases where the F-box subunit functions as a substrate-specificity determining adaptor. A comprehensive control of protein production includes global co-repressors as the conserved Ssn6(SsnF)-Tup1(RcoA) complex, which reduces transcription on multiple levels. We have identified a novel connection between protein degradation and synthesis through an F-box protein. Fbx15 can be incorporated into SCF E3 ubiquitin ligases and controls upon stress the nuclear localization of the SsnF. Fbx15 plays a critical role for A. fumigatus adaptation and is essential for virulence in a murine infection model. Fbx15 is a fungal-specific protein and therefore a potential target for future drug development. |
| Databáze: | OpenAIRE |
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