title: Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans.
abstract: The yeast-hypha transition is an important virulence trait of Candida albicans. We report that the AGC kinase Sch9 prevents hypha formation specifically under hypoxia at high CO(2) levels. sch9 mutants showed no major defects in growth and stress resistance but a striking hyperfilamentous phenotype under hypoxia (<10% O(2)), although only in the presence of elevated CO(2) levels (>1%) and at temperatures of <37°C during surface growth. The sch9 hyperfilamentous phenotype was independent of Rim15 kinase and was recreated by inhibition of Tor1 kinase by rapamycin or caffeine in a wild-type strain, suggesting that Sch9 suppression requires Tor1. Caffeine inhibition also revealed that both protein kinase A isoforms, as well as transcription factors Czf1 and Ace2, are required to generate the sch9 mutant phenotype. Transcriptomal analyses showed that Sch9 regulates most genes solely under hypoxia and in the presence of elevated CO(2). In this environment, Sch9 downregulates genes encoding cell wall proteins and nutrient transporters, while under normoxia Sch9 and Tor1 coregulate a minor fraction of Sch9-regulated genes, e.g., by inducing glycolytic genes. Other than in Saccharomyces cerevisiae, both sch9 and rim15 mutants showed decreased chronological aging under normoxia but not under hypoxia, indicating significant rewiring of the Tor1-Sch9-Rim15 pathway in C. albicans. The results stress the importance of environmental conditions on Sch9 function and establish a novel response circuitry to both hypoxia and CO(2) in C. albicans, which suppresses hypha formation but also allows efficient nutrient uptake, metabolism, and virulence.
authors.affiliation: Institut für Mikrobiologie, Molekulare Mykologie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr, Düsseldorf, Germany.
authors.forename: Catrin
authors.initials: C
authors.lastname: Stichternoth
authors.forename: Alida
authors.initials: A
authors.lastname: Fraund
authors.forename: Eleonora
authors.initials: E
authors.lastname: Setiadi
authors.forename: Luc
authors.initials: L
authors.lastname: Giasson
authors.forename: Anna
authors.initials: A
authors.lastname: Vecchiarelli
authors.forename: Joachim F
authors.initials: JF
authors.lastname: Ernst
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002176:Candida albicans / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development* / Q000472:pathogenicity; D002245:Carbon Dioxide; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D025301:Hyphae / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D009024:Morphogenesis; D010100:Oxygen; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000935:Antifungal Agents; D005656:Fungal Proteins; D002245:Carbon Dioxide; D011494:Protein Kinases; C071569:SCH9 protein kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D010100:Oxygen