A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans

English version

Autoři: Anaïs Burgain ^aff001; Émilie Pic ^aff001; Laura Markey ^aff003; Faiza Tebbji ^aff001; Carol A. Kumamoto ^aff004; Adnane Sellam ^aff001
Působiště autorů: CHU de Québec Research Center (CHUQ), Université Laval, Quebec City, Quebec, Canada ^aff001; Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada ^aff002; Program in Molecular Microbiology, Tufts University, Boston, Massachusetts, United States of America ^aff003; Department of Molecular Biology and Microbiology, Tufts University, Boston, Massachusetts, United States of America ^aff004; Big Data Research Centre (BDRC-UL), Université Laval, Faculty of Sciences and Engineering, Quebec City, Quebec, Canada ^aff005
Vyšlo v časopise: A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1007823
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007823

Souhrn

Inside the human host, the pathogenic yeast Candida albicans colonizes predominantly oxygen-poor niches such as the gastrointestinal and vaginal tracts, but also oxygen-rich environments such as cutaneous epithelial cells and oral mucosa. This suppleness requires an effective mechanism to reversibly reprogram the primary metabolism in response to oxygen variation. Here, we have uncovered that Snf5, a subunit of SWI/SNF chromatin remodeling complex, is a major transcriptional regulator that links oxygen status to the metabolic capacity of C. albicans. Snf5 and other subunits of SWI/SNF complex were required to activate genes of carbon utilization and other carbohydrates related process specifically under hypoxia. snf5 mutant exhibited an altered metabolome reflecting that SWI/SNF plays an essential role in maintaining metabolic homeostasis and carbon flux in C. albicans under hypoxia. Snf5 was necessary to activate the transcriptional program linked to both commensal and invasive growth. Accordingly, snf5 was unable to maintain its growth in the stomach, the cecum and the colon of mice. snf5 was also avirulent as it was unable to invade Galleria larvae or to cause damage to human enterocytes and murine macrophages. Among candidates of signaling pathways in which Snf5 might operate, phenotypic analysis revealed that mutants of Ras1-cAMP-PKA pathway, as well as mutants of Yak1 and Yck2 kinases exhibited a similar carbon flexibility phenotype as did snf5 under hypoxia. Genetic interaction analysis indicated that the adenylate cyclase Cyr1, a key component of the Ras1-cAMP pathway interacted genetically with Snf5. Our study yielded new insight into the oxygen-sensitive regulatory circuit that control metabolic flexibility, stress, commensalism and virulence in C. albicans.

Klíčová slova:

Candida albicans – Carbohydrate metabolism – Hypoxia – Oxygen – Oxygen metabolism – Regulator genes – Saccharomyces cerevisiae – Transcriptional control

Zdroje

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