The Aspergillus fumigatus Damage Resistance Protein Family Coordinately Regulates Ergosterol Biosynthesis and Azole Susceptibility
Open accessAbstract
Ergosterol is a major and specific component of the fungal plasma membrane, and thus, the cytochrome P450 enzymes (Erg proteins) that catalyze ergosterol synthesis have been selected as valuable targets of azole antifungals. However, the opportunistic pathogen Aspergillus fumigatus has developed worldwide resistance to azoles largely through mutations in the cytochrome P450 enzyme Cyp51 (Erg11). In this study, we demonstrate that a cytochrome b 5 -like heme-binding damage resistance protein (Dap) family, comprised of DapA, DapB, and DapC, coordinately regulates the functionality of cytochrome P450 enzymes Erg5 and Erg11 and oppositely affects susceptibility to azoles. The expression of all three genes is induced in an azole concentration-dependent way, and the decreased susceptibility to azoles requires DapA stabilization of cytochrome P450 protein activity. In contrast, overexpression of DapB and DapC causes dysfunction of Erg5 and Erg11, resulting in abnormal accumulation of sterol intermediates and further accentuating the sensitivity of Δ dapA strains to azoles. The results of exogenous-hemin rescue and heme-binding-site mutagenesis experiments demonstrate that the heme binding of DapA contributes the decreased azole susceptibility, while DapB and -C are capable of reducing the activities of Erg5 and Erg11 through depletion of heme. In vivo data demonstrate that inactivated DapA combined with activated DapB yields an A. fumigatus mutant that is easily treatable with azoles in an immunocompromised mouse model of invasive pulmonary aspergillosis. Compared to the single Dap proteins found in Saccharomyces cerevisiae and Schizosaccharomyces pombe , we suggest that this complex Dap family regulatory system emerged during the evolution of fungi as an adaptive means to regulate ergosterol synthesis in response to environmental stimuli. IMPORTANCE Knowledge of the ergosterol biosynthesis route in fungal pathogens is useful in the design of new antifungal drugs and could aid in the study of antifungal-drug resistance mechanisms. In this study, we demonstrate that three cytochrome b 5 -like Dap proteins coordinately regulate the azole resistance and ergosterol biosynthesis catalyzed by cytochrome P450 proteins. Our new insights into the Dap regulatory system in fungal pathogens may have broad therapeutic ramifications beyond their usefulness for classic azole antifungals. Moreover, our elucidation of the molecular mechanism of Dap regulation of cytochrome P450 protein functionality through heme-binding activity may extend beyond the Kingdom Fungi with applicability toward Dap protein regulation of mammalian sterol synthesis.
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Antifungals: mechanism of action, resistance, and therapeutic perspectives
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- Authors
- Song, J., Zhai, P., Zhang, Y., Zhang, C., Sang, H., Han, G., Keller, N. P., & Lu, L.
- Affiliations
- Nanjing Normal University (CN)
- Nanjing General Hospital of Nanjing Military Command (CN)
- Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, China
- University of Wisconsin–Madison (US)
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2016-03-02
- Volume
- 7
- Issue
- 1
- Pages
- e01919-15
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC4791848
- OpenAlex
- W2278844018
- Cited by
- 73
- References
- 52
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 14 · 2020: 9 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 3
- FWCI
- 6.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- The Special Fund for the Doctoral Program of Higher Education of China (No. 20123207110012)
- Innovation Project for College Graduates of Jiangsu Province (No. CXZZ13_0415)
- Excellent Doctoral Dissertation Special Fund of Nanjing Normal University (No. 1812000002140)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Aspergillus fumigatus, DAPA, DAPC, ergosterol biosynthesis, azole resistance, cytochrome P450, ERG11, heme binding, antifungal resistance, invasive pulmonary aspergillosis, sterol intermediates
- MeSH terms
- Heme-Binding Proteins, Animals, Antifungal Agents, Aspergillus fumigatus, Azoles, Carrier Proteins, Cytochrome P-450 Enzyme System, Disease Models, Animal, DNA, Fungal, Ergosterol, Fungal Proteins, Heme, Hemeproteins, Mutation, Gene Expression Regulation, Fungal, Immunocompromised Host, Drug Resistance, Fungal, Mice, Pulmonary Aspergillosis
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