Candida albicans Msi3p, a homolog of the Saccharomyces cerevisiae Sse1p of the Hsp70 family, is involved in cell growth and fluconazole tolerance.
We investigated the cellular function of Msi3p, belonging to the heat shock protein 70 family, in Candida albicans. The mutant strain tetMSI3 was generated, in which MSI3 was controlled by a tetracycline-repressive promoter, because there is evidence to suggest that MSI3 is an essential gene. We controlled the MSI3 expression level by doxycycline (DOX) and compared its phenotype with that of a control strain with the tetracycline-repressive promoter and a wild-type copy MSI3. The results indicated that MSI3 was essential for cell growth. In addition, all the tetMSI3-infected mice survived after DOX administration. Drug susceptibility tests indicated that repression of MSI3 expression resulted in hypersensitivity to fluconazole and conferred fungicidal activity to fluconazole. The expression levels of MSI3 and calcineurin-dependent genes were upregulated in response to fluconazole in the control strain. In tetMSI3, the upregulation of MSI3 was lost, and the expression level of the calcineurin-dependent genes was no longer elevated in response to fluconazole and was not affected by DOX, indicating that the upregulation of MSI3 expression was required for the induction of the calcineurin-dependent gene expression. These data suggest that Msi3p confers fluconazole tolerance by partially influencing the calcineurin signaling pathway and also other tolerance mechanisms.
Division of Biomedical Sciences, Department of Functional Bioscience, Section of Infection Biology, Fukuoka Dental College, Fukuoka, Japan.
Jun-ichi
J
Nagao
Tamaki
T
Cho
Jun
J
Uno
Keigo
K
Ueno
Rieko
R
Imayoshi
Hironobu
H
Nakayama
Hiroji
H
Chibana
Hidenori
H
Kaminishi
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development*; D002177:Candidiasis / Q000382:microbiology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage / Q000378:metabolism; D004361:Drug Tolerance; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D020043:Genes, Essential; D005800:Genes, Fungal; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D051379:Mice; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D016019:Survival Analysis
D000935:Antifungal Agents; D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; C494656:SSE1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015725:Fluconazole; D004318:Doxycycline