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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.

SUBMITTER: Stichternoth C

PROVIDER: S-EPMC3127645 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans.

Stichternoth Catrin C Fraund Alida A Setiadi Eleonora E Giasson Luc L Vecchiarelli Anna A Ernst Joachim F JF

Eukaryotic cell 20110218 4

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 ...[more]

PMID: 21335533

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Project description:UnlabelledpH homeostasis is critical for all organisms; in the fungal pathogen Candida albicans, pH adaptation is critical for virulence in distinct host niches. We demonstrate that beyond adaptation, C. albicans actively neutralizes the environment from either acidic or alkaline pHs. Under acidic conditions, this species can raise the pH from 4 to >7 in less than 12 h, resulting in autoinduction of the yeast-hyphal transition, a critical virulence trait. Extracellular alkalinization has been reported to occur in several fungal species, but under the specific conditions that we describe, the phenomenon is more rapid than previously observed. Alkalinization is linked to carbon deprivation, as it occurs in glucose-poor media and requires exogenous amino acids. These conditions are similar to those predicted to exist inside phagocytic cells, and we find a strong correlation between the use of amino acids as a cellular carbon source and the degree of alkalinization. Genetic and genomic approaches indicate an emphasis on amino acid uptake and catabolism in alkalinizing cells. Mutations in four genes, STP2, a transcription factor regulating amino acid permeases, ACH1 (acetyl-coenzyme A [acetyl-CoA] hydrolase), DUR1,2 (urea amidolyase), and ATO5, a putative ammonia transporter, abolish or delay neutralization. The pH changes are the result of the extrusion of ammonia, as observed in other fungi. We propose that nutrient-deprived C. albicans cells catabolize amino acids as a carbon source, excreting the amino nitrogen as ammonia to raise environmental pH and stimulate morphogenesis, thus directly contributing to pathogenesis.ImportanceCandida albicans is the most important fungal pathogen of humans, causing disease at multiple body sites. The ability to switch between multiple morphologies, including a rounded yeast cell and an elongated hyphal cell, is a key virulence trait in this species, as this reversible switch is thought to promote dissemination and tissue invasion in the host. We report here that C. albicans can actively alter the pH of its environment and induce its switch to the hyphal form. The change in pH is caused by the release of ammonia from the cells produced during the breakdown of amino acids. This phenomenon is unprecedented in a human pathogen and may substantially impact host physiology by linking morphogenesis, pH adaptation, carbon metabolism, and interactions with host cells, all of which are critical for the ability of C. albicans to cause disease.

Dataset Information

Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans.

Publications

Sch9 kinase integrates hypoxia and CO2 sensing to suppress hyphal morphogenesis in Candida albicans.

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