Linking Sfl1 Regulation of Hyphal Development to Stress Response Kinases in Candida albicans

Abstract

Candida albicans is an important human pathogen responsible for causing both superficial and systemic infections. Its ability to switch from the yeast form to the hyphal growth form is required for its pathogenicity. Acidic pH inhibits hyphal initiation, but the nature of the mechanism for this inhibition is not completely clear. We show that acidic pH represses hyphal initiation independently of the temperature- and farnesol-mediated Nrg1 downregulation. Using a collection of transcription factor deletion mutants, we observed that the sfl1 mutant induced hyphae in acidic pH but not in farnesol at 37°C. Furthermore, transcription of hyphal regulators BRG1 and UME6 was not induced in wild-type (WT) cells but was induced in the sfl1 mutant during hyphal induction in acidic pH. Using the same screening conditions with the collection of kinase mutants, we found that deletions of the core stress response mitogen-activated protein (MAP) kinase HOG1 and its kinase PBS2, the cell wall stress MAP kinase MKC1, and the calcium/calmodulin-dependent kinase CMK1 allowed hyphal initiation in acidic pH. Furthermore, Hog1 phosphorylation induced by high osmotic stress also retarded hyphal initiation, and the effect was abolished in the sfl1 and three kinase mutants but was enhanced in the phosphatase mutant ptp2 ptp3. We also found functional associations among Cmk1, Hog1, and Sfl1 for cation stress. Our study results suggest that robust hyphal initiation requires downregulation of both Nrg1 and Sfl1 transcriptional repressors as well as timely BRG1 expression. Acidic pH and cationic stress retard hyphal initiation via the stress-responsive kinases and Sfl1. IMPORTANCE Candida albicans is a commensal as well as a pathogen of humans. C. albicans is able to mount a cellular response to a diverse range of external stimuli in the host and switch reversibly between the yeast and hyphal growth forms. Hyphal development is a key virulence determinant. Here, we studied how C. albicans senses different environmental signals to control its growth forms. Our study results suggest that robust hyphal development requires downregulation of two transcriptional repressors, Nrg1 and Sfl1. Acidic pH or cationic stress inhibits hyphal formation via stress-responsive kinases and Sfl1.

Three-Dimensional Genome Map of the Filamentous Fungus Penicillium oxalicum

“…SPT23 regulates lipid desaturation and ergosterol biosynthesis, playing an important role in the ability of yeast cells to adapt to environmental changes ( 42 , 43 ). SFL1 is involved in acidic biofilm formation and hyphal development in the pathogenic yeast Candida albicans ( 44 , 45 ) and in determining virulence and heat tolerance in the phytopathogenic filamentous fungus Magnaporthe oryzae ( 46 ). To date, there have been no reports of the effects of SPT23 and SFL1 on the expression of cellulase and xylanase genes in fungi, and further study is therefore needed.…”

Genetic Analysis of Candida albicans Filamentation by the Iron Chelator BPS Reveals a Role for a Conserved Kinase—WD40 Protein Pair

“…Sfl1 is a repressor of hyphal morphogenesis [50,70], which was suggested to antagonize Flo8 [50] as well as Sfl2 [51]. It was suggested to be centrally involved in the formation of biofilm-like microcolonies on an oral mucosa model, together with Sfl2, Rob1, and Ndt80 [71], and to suppress hyphal formation in an acidic medium [72]. In our hands, Sfl1 was indeed found to be differentially modified in wild-type vs. yak1 −/− or orf19.384 −/− cells, even in normal yeast growth medium.…”

Hog1-mediated stress tolerance in the pathogenic fungus Trichosporon asahii

“…Role of the hog1 gene in hyphal formation by T. asahii T. asahii has several morphologic forms, including yeast, hyphae ( lament form), and arthroconidia (chains of cells and asexual spores) 4 . In C. albicans, Hog1 is a key factor that regulates hyphal formation 20,21,23,[25][26][27][28]46 . We examined whether hog1 gene de ciency affects hyphal formation in T. asahii.…”

“…The Hog1 protein is also involved in the pathogenicity of C. albicans to the host by increasing its resistance to various stressors and control of the morphologic transformation from yeast to mycelium [20][21][22][23][24] . Moreover, stress response systems are related to morphologic changes of C. albicans [25][26][27][28] . The role of Hog1 in the stress tolerance and virulence of T. asahii, however, remains unknown.…”