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Toolsvan Rhijn, Norman, Zhao, Can, Al-Furaji, Narjes, Storer, Isabelle S. R., Valero, Clara, Gago, Sara, Chown, Harry, Baldin, Clara, Grant, Rachael Fortune, Bin Shuraym, Hajer, Ivanova, Lia, Kniemeyer, Olaf, Krüger, Thomas, Bignell, Elaine, Goldman, Gustavo H., Amich, Jorge, Delneri, Daniela, Bowyer, Paul, Brakhage, Axel A., Haas, Hubertus and Bromley, Michael J. (2024) Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging. Nature Communications, 15. ISSN 2041-1723
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Abstract
More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.
| Item Type: | Article |
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| Additional Information: | Data availability: Mass spectrometry proteomics data are available from the ProteomeXchange Consortium via the PRIDE partner repository with dataset identifier PXD042616. Source data are provided with this paper. Funding information: This work was funded by the Wellcome Trust under project numbers 208396/Z/17/Z (to M.J.B., P.B. and D.D.) and 219551/Z/19/Z (to M.J.B.). Additional funds were received from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Collaborative Research Centre/Transregio FungiNet 124 ‘Pathogentic fungi and their human host: Networks of Interaction’ (project number 210879364; project A1 and Z2) (to A.A.B.) and the International Leibniz Research School (ILRS) for Microbial and Biomolecular Interactions as part of the excellence graduate school Jena School for Microbial Communication (JSMC) (to A.A.B.). We thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) 2021/04977-5 (to G.H.G.) and 2020/01131-5 and 2018/00715-3 (to C.V.) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) 301058/2019-9 and 404735/2018-5 (to G.H.G.), both from Brazil, and also a National Institutes of Health National Institute of Allergy and Infectious Diseases grant (R01AI153356) from the United States (to G.H.G.). The Ministry of Higher Education and Scientific Research (MOHESR), Iraq. to N.A.F and M.B. |
| Uncontrolled Keywords: | chemistry(all),biochemistry, genetics and molecular biology(all),general,physics and astronomy(all) ,/dk/atira/pure/subjectarea/asjc/1600 |
| Faculty \ School: | Faculty of Science > School of Chemistry, Pharmacy and Pharmacology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 20 Aug 2025 14:30 |
| Last Modified: | 27 Aug 2025 08:28 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/100177 |
| DOI: | 10.1038/s41467-024-48592-8 |
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