Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.

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...

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Autores: van Rhijn, Norman, Zhao, Can, Al-Furaiji, 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, Bromley, Michael J
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26261
Acceso en línea:https://hdl.handle.net/20.500.12105/26261
Access Level:acceso abierto
Palabra clave:Animals
Antifungal Agents
Aspergillosis
Aspergillus fumigatus
Azoles
Dyrk Kinases
Female
Fungal Proteins
Lung
Mice
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spelling Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.van Rhijn, NormanZhao, CanAl-Furaiji, NarjesStorer, Isabelle S RValero, ClaraGago, SaraChown, HarryBaldin, ClaraGrant, Rachael-FortuneBin Shuraym, HajerIvanova, LiaKniemeyer, OlafKrüger, ThomasBignell, ElaineGoldman, Gustavo HAmich, JorgeDelneri, DanielaBowyer, PaulBrakhage, Axel AHaas, HubertusBromley, Michael JAnimalsAntifungal AgentsAspergillosisAspergillus fumigatusAzolesDyrk KinasesFemaleFungal ProteinsLungMiceMore 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.Nature Publishing GroupWellcome TrustDeutsche Forschungsgemeinschaft (Alemania)Fundação de Amparo à Pesquisa do Estado de São Paulo Minas Gerais (Brasil)São Paulo Research FoundationNational Council for Scientific and Technological Development (Brasil)NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos)Ministry of Higher Education and Scientific Research (Iraq)20252025-02-0520242024-06-1120242024-06-11research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfapplication/pdfapplication/octet-streamhttps://hdl.handle.net/20.500.12105/26261reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/262612026-06-12T12:43:37Z
dc.title.none.fl_str_mv Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
title Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
spellingShingle Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
van Rhijn, Norman
Animals
Antifungal Agents
Aspergillosis
Aspergillus fumigatus
Azoles
Dyrk Kinases
Female
Fungal Proteins
Lung
Mice
title_short Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
title_full Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
title_fullStr Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
title_full_unstemmed Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
title_sort Functional analysis of the Aspergillus fumigatus kinome identifies a druggable DYRK kinase that regulates septal plugging.
dc.creator.none.fl_str_mv van Rhijn, Norman
Zhao, Can
Al-Furaiji, 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
Bromley, Michael J
author van Rhijn, Norman
author_facet van Rhijn, Norman
Zhao, Can
Al-Furaiji, 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
Bromley, Michael J
author_role author
author2 Zhao, Can
Al-Furaiji, 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
Bromley, Michael J
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Wellcome Trust
Deutsche Forschungsgemeinschaft (Alemania)
Fundação de Amparo à Pesquisa do Estado de São Paulo Minas Gerais (Brasil)
São Paulo Research Foundation
National Council for Scientific and Technological Development (Brasil)
NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos)
Ministry of Higher Education and Scientific Research (Iraq)
dc.subject.none.fl_str_mv Animals
Antifungal Agents
Aspergillosis
Aspergillus fumigatus
Azoles
Dyrk Kinases
Female
Fungal Proteins
Lung
Mice
topic Animals
Antifungal Agents
Aspergillosis
Aspergillus fumigatus
Azoles
Dyrk Kinases
Female
Fungal Proteins
Lung
Mice
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-06-11
2024
2024-06-11
2025
2025-02-05
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/26261
url https://hdl.handle.net/20.500.12105/26261
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
application/octet-stream
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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