Clotrimazole-Induced Oxidative Stress Triggers Novel Yeast Pkc1-Independent Cell Wall Integrity MAPK Pathway Circuitry

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dc.contributor.authorSellers Moya, Ángela
dc.contributor.authorNuévalos, Marcos
dc.contributor.authorMolina Martín, María
dc.contributor.authorMartín Brieva, Humberto
dc.date.accessioned2023-06-16T14:22:27Z
dc.date.available2023-06-16T14:22:27Z
dc.date.issued2021-08-09
dc.description.abstractAzoles are one of the most widely used drugs to treat fungal infections. To further understand the fungal response to azoles, we analyzed the MAPK circuitry of the model yeast Saccharomyces cerevisiae that operates under treatment with these antifungals. Imidazoles, and particularly clotrimazole, trigger deeper changes in MAPK phosphorylation than triazoles, involving a reduction in signaling through the mating pathway and the activation of the MAPKs Hog1 and Slt2 from the High-Osmolarity Glycerol (HOG) and the Cell Wall Integrity (CWI) pathways, respectively. Clotrimazole treatment leads to actin aggregation, mitochondrial alteration, and oxidative stress, which is essential not only for the activation of both MAPKs, but also for the appearance of a low-mobility form of Slt2 caused by additional phosphorylation to that occurring at the conserved TEY activation motif. Clotrimazole-induced ROS production and Slt2 phosphorylation are linked to Tpk3-mediated PKA activity. Resistance to clotrimazole depends on HOG and CWI-pathway-mediated stress responses. However, Pkc1 and other proteins acting upstream in the pathway are not critical for the activation of the Slt2 MAPK module, suggesting a novel rewiring of signaling through the CWI pathway. We further show that the strong impact of azole treatment on MAPK signaling is conserved in other yeast species.
dc.description.departmentDepto. de Microbiología y Parasitología
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)
dc.description.sponsorshipComunidad de Madrid/FEDER
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/71872
dc.identifier.doi10.3390/jof7080647
dc.identifier.issn2309-608X
dc.identifier.officialurlhttps://doi.org/10.3390/jof7080647
dc.identifier.relatedurlhttps://www.mdpi.com/journal/jof
dc.identifier.urihttps://hdl.handle.net/20.500.14352/4858
dc.issue.number8
dc.journal.titleJournal of Fungi
dc.language.isoeng
dc.page.initial647
dc.publisherMDPI
dc.relation.projectIDPID2019-105342GB-I00
dc.relation.projectIDInGEMICS-CM (B2017/BMD3691)
dc.rightsAtribución 3.0 España
dc.rights.accessRightsopen access
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/es/
dc.subject.cdu579
dc.subject.keywordYeast
dc.subject.keywordCell wall integrity
dc.subject.keywordMAPK
dc.subject.keywordPhosphorylation
dc.subject.keywordAzoles
dc.subject.keywordClotrimazole
dc.subject.ucmMicrobiología (Farmacia)
dc.subject.unesco3302.03 Microbiología Industrial
dc.titleClotrimazole-Induced Oxidative Stress Triggers Novel Yeast Pkc1-Independent Cell Wall Integrity MAPK Pathway Circuitry
dc.typejournal article
dc.volume.number7
dspace.entity.typePublication
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relation.isAuthorOfPublication2c8197a0-783e-462f-b59c-95c3b2e9fc3f
relation.isAuthorOfPublication44984b59-886b-441f-a869-1aa94cee080d
relation.isAuthorOfPublication.latestForDiscoverydf46f90d-579d-48d9-8a2f-f299a317eba2
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