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The transcription factor Flo8 mediates CO2 sensing in the human fungal pathogen Candida albicans.

ABSTRACT: Physiological levels of CO(2) have a profound impact on prominent biological attributes of the major fungal pathogen of humans, Candida albicans. Elevated CO(2) induces filamentous growth and promotes white-to-opaque switching. However, the underlying molecular mechanisms of CO(2) sensing in C. albicans are insufficiently understood. Here we identify the transcription factor Flo8 as a key regulator of CO(2)-induced morphogenesis in C. albicans by screening a gene null mutant library. We show that Flo8 is required for CO(2)-induced white-to-opaque switching, as well as for filamentous growth. Ectopic expression of FLO8 hypersensitizes C. albicans cells to the elevated CO(2) levels. Furthermore, we demonstrate that CO(2) signaling in C. albicans involves two pathways: the already reported cAMP/protein kinase A and another major one that is unidentified. The two pathways converge on the transcription factor Flo8, which is the master regulator of CO(2) sensing in C. albicans and plays a critical role in regulation of white-to-opaque switching and filamentous growth. Our findings provide new insights into the understanding of CO(2) sensing in pathogenic fungi that have important implications for higher organisms.

SUBMITTER: Du H

PROVIDER: S-EPMC3395658 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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The transcription factor Flo8 mediates CO2 sensing in the human fungal pathogen Candida albicans.

Du Han H Guan Guobo G Xie Jing J Cottier Fabien F Sun Yuan Y Jia Wei W Mühlschlegel Fritz A FA Huang Guanghua G

Molecular biology of the cell 20120523 14

Physiological levels of CO(2) have a profound impact on prominent biological attributes of the major fungal pathogen of humans, Candida albicans. Elevated CO(2) induces filamentous growth and promotes white-to-opaque switching. However, the underlying molecular mechanisms of CO(2) sensing in C. albicans are insufficiently understood. Here we identify the transcription factor Flo8 as a key regulator of CO(2)-induced morphogenesis in C. albicans by screening a gene null mutant library. We show tha ...[more]

PMID: 22621896

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Project description:The yeast-to-hyphal morphotype transition and subsequent biofilm formation are important virulence factors of Candida albicans and are closely associated with ergosterol biosynthesis. Flo8 is an important transcription factor that determines filamentous growth and biofilm formation in C. albicans. However, the relationship between Flo8 and regulation of the ergosterol biosynthesis pathway remains elusive. Here, we analyzed the sterol composition of a flo8-deficient C. albicans strain by gas chromatography-mass spectrometry and observed the accumulation of the sterol intermediate zymosterol, the substrate of Erg6 (C-24 sterol methyltransferase). Accordingly, the transcription level of ERG6 was reduced in the flo8-deficient strain. Yeast one-hybrid experiments revealed that Flo8 physically interacted with the ERG6 promoter. Ectopic overexpression of ERG6 in the flo8-deficient strain partially restored biofilm formation and in vivo virulence in a Galleria mellonella infection model. These findings suggest that Erg6 is a downstream effector of the transcription factor Flo8 that mediates the cross talk between sterol synthesis and virulence factors in C. albicans. IMPORTANCE Biofilm formation by C. albicans hinders its eradication by immune cells and antifungal drugs. Flo8 is an important morphogenetic transcription factor that regulates the biofilm formation and in vivo virulence of C. albicans. However, little is known about how Flo8 regulates biofilm formation and fungal pathogenicity. Here, we determined that Flo8 directly binds to the promoter of ERG6 to positively regulate its transcriptional expression. Consistently, loss of flo8 results in the accumulation of the substrate of Erg6. Moreover, ectopic overexpression of ERG6 at least partially restores the biofilm formation and virulence of the flo8-deficient strain both in vitro and in vivo. This work provides a new perspective on the metabolic link between transcription factors and morphotypes in C. albicans.

Dataset Information

The transcription factor Flo8 mediates CO2 sensing in the human fungal pathogen Candida albicans.

Publications

The transcription factor Flo8 mediates CO2 sensing in the human fungal pathogen Candida albicans.

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