Cargando…

Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility

Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diver...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Yunjin, Liston, Sean D., Lee, Dongyeob, Robbins, Nicole, Cowen, Leah E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160768/
https://www.ncbi.nlm.nih.gov/pubmed/35663022
http://dx.doi.org/10.1016/j.isci.2022.104432
_version_ 1784719339445813248
author Lee, Yunjin
Liston, Sean D.
Lee, Dongyeob
Robbins, Nicole
Cowen, Leah E.
author_facet Lee, Yunjin
Liston, Sean D.
Lee, Dongyeob
Robbins, Nicole
Cowen, Leah E.
author_sort Lee, Yunjin
collection PubMed
description Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diverse diseases, yet kinases remain untapped in the quest for new antifungals. Here, we performed a comprehensive analysis of the C. albicans kinome to identify genes for which loss-of-function confers hypersensitivity to the two most widely deployed antifungals, echinocandins and azoles. Through this analysis, we found a role for the casein kinase 1 (CK1) homologue Hrr25 in regulating tolerance to both antifungals as well as target-mediated echinocandin resistance. Follow-up investigations established that Hrr25 regulates these responses through its interaction with the SBF transcription factor. Thus, we provide insights into the circuitry governing cellular responses to antifungals and implicate Hrr25 as a key mediator of drug resistance.
format Online
Article
Text
id pubmed-9160768
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-91607682022-06-03 Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility Lee, Yunjin Liston, Sean D. Lee, Dongyeob Robbins, Nicole Cowen, Leah E. iScience Article Candida albicans is a leading cause of death due to systemic fungal infections. Poor patient outcomes are attributable to the limited number of antifungal classes and the increasing prevalence of drug resistance. Protein kinases have emerged as rewarding targets in the development of drugs for diverse diseases, yet kinases remain untapped in the quest for new antifungals. Here, we performed a comprehensive analysis of the C. albicans kinome to identify genes for which loss-of-function confers hypersensitivity to the two most widely deployed antifungals, echinocandins and azoles. Through this analysis, we found a role for the casein kinase 1 (CK1) homologue Hrr25 in regulating tolerance to both antifungals as well as target-mediated echinocandin resistance. Follow-up investigations established that Hrr25 regulates these responses through its interaction with the SBF transcription factor. Thus, we provide insights into the circuitry governing cellular responses to antifungals and implicate Hrr25 as a key mediator of drug resistance. Elsevier 2022-05-18 /pmc/articles/PMC9160768/ /pubmed/35663022 http://dx.doi.org/10.1016/j.isci.2022.104432 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Lee, Yunjin
Liston, Sean D.
Lee, Dongyeob
Robbins, Nicole
Cowen, Leah E.
Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
title Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
title_full Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
title_fullStr Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
title_full_unstemmed Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
title_short Functional analysis of the Candida albicans kinome reveals Hrr25 as a regulator of antifungal susceptibility
title_sort functional analysis of the candida albicans kinome reveals hrr25 as a regulator of antifungal susceptibility
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160768/
https://www.ncbi.nlm.nih.gov/pubmed/35663022
http://dx.doi.org/10.1016/j.isci.2022.104432
work_keys_str_mv AT leeyunjin functionalanalysisofthecandidaalbicanskinomerevealshrr25asaregulatorofantifungalsusceptibility
AT listonseand functionalanalysisofthecandidaalbicanskinomerevealshrr25asaregulatorofantifungalsusceptibility
AT leedongyeob functionalanalysisofthecandidaalbicanskinomerevealshrr25asaregulatorofantifungalsusceptibility
AT robbinsnicole functionalanalysisofthecandidaalbicanskinomerevealshrr25asaregulatorofantifungalsusceptibility
AT cowenleahe functionalanalysisofthecandidaalbicanskinomerevealshrr25asaregulatorofantifungalsusceptibility