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Tra1 is a pseudokinase of the PIKK family characterized by a C-terminal PI3K domain with no known kinase activity. However, mutations of specific arginine residues to glutamine in the PI3K domains (an allele termed tra1Q3) result in reduced growth and increased sensitivity to multiple stresses. In the opportunistic fungal pathogen Candida albicans, the tra1Q3 allele reduces pathogenicity and increases sensitivity to the echinocandin antifungal drug caspofungin, which disrupts the fungal cell wall. Here, we found that compromised Tra1 function, in contrast to what is seen with caspofungin, increases tolerance to the azole class of antifungal drugs, which inhibits ergosterol synthesis. In C. albicans, tra1Q3 increases the expression of genes linked to azole resistance, such as ERG11 and CDR1. CDR1 encodes a multidrug ABC transporter associated with efflux of multiple xenobiotics, including azoles. Consequently, cells carrying tra1Q3 show reduced intracellular accumulation of fluconazole. In contrast, a tra1Q3 Saccharomyces cerevisiae strain displayed opposite phenotypes: decreased tolerance to azole, decreased expression of the efflux pump PDR5, and increased intracellular accumulation of fluconazole. Therefore, our data provide evidence that Tra1 differentially regulates the antifungal response across yeast species.<\/jats:p>","DOI":"10.1093\/g3journal\/jkad250","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T14:07:38Z","timestamp":1698415658000},"source":"Crossref","is-referenced-by-count":1,"title":["Evolutionary diversity of the control of the azole response by Tra1 across yeast species"],"prefix":"10.1093","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8119-8335","authenticated-orcid":false,"given":"Gabriela Marsiglio Nunes","family":"Librais","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Western Ontario , London, Ontario, N6A 5C1 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, The University of Western Ontario , London, Ontario, N6A 5C1 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iqra","family":"Razzaq","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, University of Guelph , Guelph, Ontario N1G 2W1 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8015-9668","authenticated-orcid":false,"given":"Christopher J","family":"Brandl","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The University of Western Ontario , London, Ontario, N6A 5C1 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7119-8865","authenticated-orcid":false,"given":"Rebecca S","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, University of Guelph , Guelph, Ontario N1G 2W1 , 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